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1.
Front Cell Dev Biol ; 12: 1412461, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39228402

RESUMO

Specific protein 1 (Sp1) is central to regulating transcription factor activity and cell signaling pathways. Sp1 is highly associated with the poor prognosis of various cancers; it is considered a non-oncogene addiction gene. The function of Sp1 is complex and contributes to regulating extensive transcriptional activity, apart from maintaining basal transcription. Sp1 activity and stability are affected by post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, glycosylation, and SUMOylation. These modifications help to determine genetic programs that alter the Sp1 structure in different cells and increase or decrease its transcriptional activity and DNA binding stability in response to pathophysiological stimuli. Investigating the PTMs of Sp1 will contribute to a deeper understanding of the mechanism underlying the cell signaling pathway regulating Sp1 stability and the regulatory mechanism by which Sp1 affects cancer progression. Furthermore, it will facilitate the development of new drug targets and biomarkers, thereby elucidating considerable implications in the prevention and treatment of cancer.

2.
Pest Manag Sci ; 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39180165

RESUMO

BACKGROUND: Rice blast has a significant detrimental impact on rice yields, so developing efficient biological control technologies is an effective means for rice blast prevention and control. The GroEL protein has proven to be effective at preventing and managing the pathogenicity of rice blast. RESULTS: Here, we analyzed the amino acid sequence of the GroEL protein and synthesized the '60 kDa chaperonin signature' (350-373 amino acids) peptide SP1.2, which has potent antifungal activity. Notably, the SP1.2 peptide exhibited potent fungicidal activity against Magnaporthe oryzae, effectively inhibiting appressorium germination. Electron microscopy revealed that SP1.2 disrupted the fungal plasma membrane and bound to multiple bioactive phosphoinositides in vitro, triggering the production of reactive oxygen species. Furthermore, it also caused an increase in the acetylation of M. oryzae and induced autophagy in cells. The spray application of SP1.2 significantly reduced the number of disease spots caused by the fungal pathogen M. oryzae in rice, enhancing the defense response of rice plants. Field trials showed that the control effect was 64.59% after spraying SP1.2. CONCLUSION: Our study illustrates the antifungal activity of the structurally unique SP1.2 peptide against plant fungal pathogens and paves the way for the future development of this class of peptides as antifungal agents. © 2024 Society of Chemical Industry.

3.
Genomics ; 116(5): 110923, 2024 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-39191354

RESUMO

BACKGROUND: Patients with lung adenocarcinoma (LUAD) generally have poor prognosis. The role of striatin-interacting protein 2 (STRIP2) in LUAD remain unclear. METHODS: Liquid chromatography-mass spectrometry analyses were used to screen the STRIP2-binding proteins and co-immunoprecipitation verified these interactions. A dual luciferase reporter assay explored the transcription factor activating STRIP2 transcription. Xenograft and lung metastasis models assessed STRIP2's role in tumor growth and metastasis in vivo. RESULTS: STRIP2 is highly expressed in LUAD tissues and is linked to poor prognosis. STRIP2 expression in LUAD cells significantly promoted cell proliferation, invasion, and migration in vitro and in vivo. Mechanistically, STRIP2 boosted the PI3K/AKT/mTOR/MYC cascades by binding AKT. In addition, specificity protein 1, potently activated STRIP2 transcription by binding to the STRIP2 promoter. Blocking STRIP2 reduces tumor growth and lung metastasis in xenograft models. CONCLUSIONS: Our study identifies STRIP2 is a key driver of LUAD progression and a potential therapeutic target.

4.
Gene ; 930: 148858, 2024 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-39153708

RESUMO

Gliomas are the most prevalent malignancies of the central nervous system (CNS). Downregulation of microRNA­124 (miR­124) has been identified in glioma; however, its biological functions in glioma are not yet fully understood. Specificity protein 1 (SP1) is a type of transcription factor that is involved in cancer progression. In this study, we examined the targeting of Sp1 mRNA by miR-124-3p in a rat glioma model. After confirming and selecting the binding of Sp1 to miR-124 with the help of bioinformatics methods, adult male Wistar rats were used to induce glioma by microinjection of 1 × 106 C6 cells into the striatum area of brain. The rats were divided into 3 groups; intact, sham and glioma groups. The presence of glioma was confirmed 21 days after implantation through histological analysis. The expression levels of miR-124 and SP1 genes in the experimental groups were examined using quantitative real-time polymerase chain reaction (qRT-PCR). Our data showed that the expression of miR-124 was significantly downregulated in glioma group compared to the sham and intact group, while the expression of SP1 was significantly upregulated. We found that the expression levels of miR-124 and Sp1 were decreased and increased in C6 cell line compared to the normal brain tissue cell line, respectively. The results indicated that Sp1 was identified as a direct target of miR­124 through luciferase reporter assays. In summary, this study demonstrated for the first time that miR-124 expression is downregulated and Sp1 expression is upregulated in an animal model of glioma, which, in turn, may be involved in the development of glioma brain cancer.


Assuntos
Neoplasias Encefálicas , Regulação Neoplásica da Expressão Gênica , Glioma , MicroRNAs , Ratos Wistar , Fator de Transcrição Sp1 , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Glioma/genética , Glioma/patologia , Glioma/metabolismo , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Masculino , Ratos , Linhagem Celular Tumoral , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Progressão da Doença , Regulação para Baixo
5.
Environ Toxicol ; 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39171862

RESUMO

Oxyresveratrol (OxyR) exerts biological and pharmacological effects in a variety of tumor cells, including antioxidant action, antitumor activity, and proapoptotic effects. However, the regulation of targeted signaling pathways by OxyR and the mechanism underlying these effects in human renal cell carcinoma (RCC) have been less studied. We observed that OxyR at noncytotoxic doses did not affect the growth of human RCC cells or normal kidney HK2 cells. OxyR inhibited ACHN and Caki-1 cell migration and invasion through targeting matrix metalloproteinase 1 (MMP1) expression. Analysis of clinical databases showed that high MMP1 expression is associated with lower overall survival (OS) in these cancers (p < 0.01). OxyR significantly inhibited the mRNA and protein expression of Sp1. Furthermore, luciferase assay results showed that OxyR inhibited Sp1 transcriptional activity. Additionally, OxyR preferentially suppressed the activation of ERK and PKCα. Treatment with U0126 (MEK inhibitor) or G06976 (PKCα inhibitor) clearly decreased Sp1 and MMP1 expression and inhibited RCC cell migration and invasion. In conclusion, OxyR may be a potential antitumor therapy for the inhibition of migration and invasion by controlling p-ERK/Sp1 and p-PKCα/Sp1-mediated MMP1 expression in RCC.

6.
Biomolecules ; 14(8)2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39199378

RESUMO

BACKGROUND: Accumulating evidence indicates that PSAT1 not only reprogrammed metabolic function but also exhibits "moonlighting" functions in promoting tumor malignancy. However, the underlying molecular mechanisms of PSAT1 promoting ER-negative breast cancer cell migration need further investigation. METHODS: Briefly, the PSAT1 and ITGA2 expression in cells and tissues was detected using qRT-PCR, immunofluorescence staining and western blot assay. The effect of PSAT1 and ITGA2 was verified both in vitro and in vivo. RNA-seq analysis explored a series of differently expressed genes. The regulation between SP1 and ITGA2 was investigated by ChIP analysis. RESULTS: We reported PSAT1 was highly expressed in ER-breast cancer tissues and tumor cells and positively correlated with metastasis. Moreover, RNA-seq analysis explored a series of differently expressed genes, including ITGA2, in PSAT1 overexpressed cells. Mechanistically, PSAT1 facilitated breast cancer metastasis via the p-AKT/SP1/ITGA2 axis. We further elucidated that PSAT1 promoted the entry of SP1 into the nucleus through the upregulation of p-AKT and confirmed ITGA2 is a target of SP1. In addition, enhanced cell migration was remarkably reversed by ITGA2 depletion or p-AKT inhibitor treatment. CONCLUSION: This study clarified the mechanism of PSAT1 in promoting ER-negative breast cancer metastasis, which may provide mechanistic clues for attenuating breast cancer metastasis.


Assuntos
Neoplasias da Mama , Movimento Celular , Regulação Neoplásica da Expressão Gênica , Integrina alfa2 , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-akt , Fator de Transcrição Sp1 , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Feminino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Movimento Celular/genética , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Integrina alfa2/metabolismo , Integrina alfa2/genética , Linhagem Celular Tumoral , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/genética , Animais , Camundongos , Transdução de Sinais , Camundongos Nus , Células MCF-7 , Antígenos de Superfície , Proteínas de Neoplasias
7.
Redox Biol ; 76: 103304, 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39153252

RESUMO

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.

8.
Res Pharm Sci ; 19(3): 287-302, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39035812

RESUMO

Background and purpose: The seventh most common type of cancer with increasing diagnosis rates around the world is head and neck squamous cell carcinoma (HNSCC). Specificity proteins (SPs) have been known for their role in the regulation of cellular division, growth, and apoptotic pathways in various cancers. In this work, we analyzed the expression levels of SPs in HNSCC to assess their diagnostic and prognostic biomarker potential. Experimental approach: Differential gene expression and correlation analysis methods were used to determine the top dysregulated genes in HNSCC. Functional enrichment and protein-protein interaction analyses were done with the DAVID database and Cytoscape software to understand their function and biological processes. Receiver operating test, logistic regression, and Cox regression analyses were performed to check SP genes' diagnostic and prognostic potential. Findings/Results: SP1 (LogFC = -0.27, P = 0.0013) and SP2 (LogFC = -0.20, P = 0.0019) genes were upregulated in HNSCC samples, while SP8 (LogFC = 2.57, P < 0.001) and SP9 (LogFC = 2.57, P < 0.001) genes were downregulated in cancer samples. A moderate positive correlation was observed among the expression levels of SP1, SP2, and SP3 genes. The SP8 and SP9 genes with AUC values of 0.79 and 0.75 demonstrated diagnostic potential which increased to 0.84 when both genes were assessed by logistic regression test. Also, the SP1 gene held a marginally significant prognostic potential. Conclusion and implications: Our findings clarify the potential of SP transcription factors as candidate diagnostic and prognostic biomarkers for early screening and treatment of HNSCC.

9.
Data Brief ; 55: 110565, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38952955

RESUMO

Nine heterocyclic compounds were investigated using density functional theory, molecular operating environment software, material studio, swissparam (Swiss drug design) software. In this work, the descriptors generated from the optimized compounds proved to be efficient and explain the level of reactivity of the investigated compound. The developed quantitative structure activity relationship (QSAR) model was predictive and reliable. Also, compound 9 proved to be capable of inhibiting Mt-Sp1/Matriptase (pdb id: 1eax) than other examined heterocyclic compounds. Target prediction analysis was carried out on the compound with highest binding affinity (Compound 9) and the results were reported.

10.
Int Ophthalmol ; 44(1): 316, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38969958

RESUMO

BACKGROUND: Diabetic cataract (DC) is a common complication of diabetes and its etiology and progression are multi-factorial. In this study, the roles of specific protein 1 (SP1) and fibroblast growth factor 7 (FGF7) in DC development were explored. METHODS: DC cell model was established by treating SRA01/04 cells with high glucose (HG). MTT assay was conducted to evaluate cell viability. Transwell assay and wound-healing assay were performed to assess cell migration and invasion. Western blot assay and qRT-PCR assay were conducted to measure the expression of N-cadherin, E-cadherin, Collagen I, Fibronectin, SP1 and FGF7 expression. CHIP assay and dual-luciferase reporter assay were conducted to analyze the combination between FGF7 and SP1. RESULTS: FGF7 was upregulated in DC patients and HG-induced SRA01/04 cells. HG treatment promoted SRA01/04 cell viability, migration, invasion and epithelial-mesenchymal transition (EMT), while FGF7 knockdown abated the effects. Transcription factor SP1 activated the transcription level of FGF7 and SP1 overexpression aggravated HG-induced SRA01/04 cell injury. SP1 silencing repressed HG-induced SRA01/04 cell viability, migration, invasion and EMT, but these effects were ameliorated by upregulating FGF7. Additionally, SP1 knockdown inhibited the PI3K/AKT pathway by regulating the transcription level of FGF7. CONCLUSION: Transcription factor SP1 activated the transcription level of FGF7 and the PI3K/AKT pathway to regulate HG-induced SRA01/04 cell viability, migration, invasion and EMT.


Assuntos
Movimento Celular , Sobrevivência Celular , Células Epiteliais , Transição Epitelial-Mesenquimal , Fator 7 de Crescimento de Fibroblastos , Glucose , Cristalino , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Fator de Transcrição Sp1 , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Glucose/farmacologia , Células Epiteliais/metabolismo , Fator 7 de Crescimento de Fibroblastos/metabolismo , Fator 7 de Crescimento de Fibroblastos/genética , Fator 7 de Crescimento de Fibroblastos/farmacologia , Cristalino/metabolismo , Cristalino/citologia , Catarata/metabolismo , Células Cultivadas , Regulação da Expressão Gênica
11.
Biomolecules ; 14(7)2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-39062521

RESUMO

In mammals, specificity protein 1 (SP1) was the first Cys2-His2 zinc finger transcription factor to be isolated within the specificity protein and Krüppel-like factor (Sp/KLF) gene family. SP1 regulates gene expression by binding to Guanine-Cytosine (GC)-rich sequences on promoter regions of target genes, affecting various cellular processes. Additionally, the activity of SP1 is markedly influenced by posttranslational modifications, such as phosphorylation, acetylation, glycosylation, and proteolysis. SP1 is implicated in the regulation of apoptosis, cell hypertrophy, inflammation, oxidative stress, lipid metabolism, plaque stabilization, endothelial dysfunction, fibrosis, calcification, and other pathological processes. These processes impact the onset and progression of numerous cardiovascular disorders, including coronary heart disease, ischemia-reperfusion injury, cardiomyopathy, arrhythmia, and vascular disease. SP1 emerges as a potential target for the prevention and therapeutic intervention of cardiac ailments. In this review, we delve into the biological functions, pathophysiological mechanisms, and potential clinical implications of SP1 in cardiac pathology to offer valuable insights into the regulatory functions of SP1 in heart diseases and unveil novel avenues for the prevention and treatment of cardiovascular conditions.


Assuntos
Doenças Cardiovasculares , Fator de Transcrição Sp1 , Humanos , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Animais , Regulação da Expressão Gênica
12.
Chem Biol Interact ; 400: 111161, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39053793

RESUMO

Hepatocellular carcinoma (HCC) is characterized with high recurrence and mortality, and the clinical treatments for HCC are very limited. Hepatocellular carcinoma stem cells are the root of HCC progress, recurrence, and multidrug resistance. Ovatodiolide (OVA) is a bioactive diterpenoid served as an inflammatory and immunotherapeutic responses modulator. In this research, we found OVA inhibited HCC stemness through inhibiting MTDH gene transcription. Moreover, we firstly discovered transcription factor SP1 bound to the promoter region of MTDH to transcriptionally regulate MTDH level. Mechanically, we demonstrated OVA decreased SP1 protein stability to transcriptionally inhibit MTDH gene, and inhibited the nuclear translocation of p65, and then diminished IL-6 level to suppress JAK/STAT3 signaling pathway, eventually decreases CD133 level and the stemness of HCC. Furthermore, we demonstrated ACT004, OVA derivative with high metabolic stability towards cytochrome P450 enzymes, showed no genotoxicity and no accumulative or delayed toxicities after long-term administration in rats. And the in vivo efficacy experiments indicated ACT004 inhibited tumor growth of hepatocellular carcinoma. In conclusion, we revealed the mechanism of OVA in regulating HCC stemness, detected the toxicity of OVA derivative and evaluated the in vivo efficacy which lays a foundation for further discovery of anti-HCC stem cell agents and provide a new strategy for the application of OVA in clinical treatment.


Assuntos
Carcinoma Hepatocelular , Diterpenos , Neoplasias Hepáticas , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Humanos , Masculino , Ratos , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Diterpenos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo
13.
Cell Rep Med ; 5(7): 101630, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38955178

RESUMO

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 µg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 µg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Masculino , Pessoa de Meia-Idade , Glioma/tratamento farmacológico , Glioma/patologia , Adulto , Feminino , Idoso , Administração Oral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Idoso de 80 Anos ou mais , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Gradação de Tumores , Dose Máxima Tolerável
14.
Cell Rep ; 43(8): 114554, 2024 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-39083378

RESUMO

The mild hypothermia response (MHR) maintains organismal homeostasis during cold exposure and is thought to be critical for the neuroprotection documented with therapeutic hypothermia. To date, little is known about the transcriptional regulation of the MHR. We utilize a forward CRISPR-Cas9 mutagenesis screen to identify the histone lysine methyltransferase SMYD5 as a regulator of the MHR. SMYD5 represses the key MHR gene SP1 at euthermia. This repression correlates with temperature-dependent levels of histone H3 lysine 26 trimethylation (H3K36me3) at the SP1 locus and globally, indicating that the mammalian MHR is regulated at the level of histone modifications. We have identified 37 additional SMYD5-regulated temperature-dependent genes, suggesting a broader MHR-related role for SMYD5. Our study provides an example of how histone modifications integrate environmental cues into the genetic circuitry of mammalian cells and provides insights that may yield therapeutic avenues for neuroprotection after catastrophic events.


Assuntos
Histona-Lisina N-Metiltransferase , Histonas , Animais , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Humanos , Camundongos , Hipotermia/metabolismo , Hipotermia/genética , Metilação , Sistemas CRISPR-Cas/genética , Regulação da Expressão Gênica , Células HEK293
15.
Biochem Genet ; 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39048769

RESUMO

Esophageal cancer (EC), a prevalent malignancy, has a high incidence and mortality. X-ray repair cross complementing 2 (XRCC2) functions on DNA damage and repair that works the progression of various cancers. Nevertheless, the role and mechanism of XRCC2 remain unknown in EC. The XRCC2 expression was examined by reverse transcription quantitative polymerase chain reaction and western blot. The function of XRCC2 in EC were investigated through cell counting kit-8, colony formation, transwell, flow cytometry, chromatin immunoprecipitation, luciferase, and western blot experiments. Besides, the role of XRCC2 in EC was assessed by western blot and immunohistochemistry experiments after nude mice were injected with EC109 cells and treated with nab-paclitaxel. The XRCC2 expression was upregulated in EC. Knockdown of XRCC2 diminished cell viability, and the number of colonies, migration cells and invasion cells of KYSE150 and EC109 cells. Silencing of XRCC2 diminished the cell viability of both two cells with a lower IC50, whereas boosted the apoptosis rate of both cells with the treatment of albumin-paclitaxel. All these outcomes were reverse with the upregulation of XRCC2 in both two cells. Mechanically, XRCC2 was transcriptionally regulated by specificity protein 1 (SP1), and silencing of SP1 inhibited the cell growth of EC. In vivo, transfection of shXRCC2 with or without albumin-paclitaxel treatment both decreased the tumor size and weight, as well as the expression of XRCC2 and Ki-67 in xenografted mice. XRCC2 transcriptionally regulated by SP2 promoted proliferation, migration, invasion, and chemoresistance of EC cells.

16.
J Orthop Surg Res ; 19(1): 396, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982418

RESUMO

BACKGROUND: The progression of osteoporosis (OP) can dramatically increase the risk of fractures, which seriously disturb the life of elderly individuals. Specific protein 1 (SP1) is involved in OP progression. However, the mechanism by which SP1 regulates OP progression remains unclear. OBJECTIVE: This study investigated the mechanism underlying the function of SP1 in OP. METHODS: SAMP6 mice were used to establish an in vivo model of age-dependent OP, and BALB/c mice were used as controls. BMSCs were extracted from two subtypes of mice. Hematoxylin and eosin staining were performed to mark the intramedullary trabecular bone structure to evaluate histological changes. ChIP assay was used to assess the targeted regulation between SP1 and miR-133a-3p. The binding sites between MAPK3 and miR-133a-3p were verified using a dual-luciferase reporter assay. The mRNA levels of miR-133a-3p and MAPK3 were detected using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The protein expression of SP1, MAPK3, Colla1, OCN, and Runx2 was examined using Western blotting. Alkaline phosphatase (ALP) kit and Alizarin Red S staining were used to investigate ALP activity and mineralized nodules, respectively. RESULTS: The levels of SP1 and miR-133a-3p were upregulated, whereas the expression of MAPK3 was downregulated in BMSCs from SAMP6 mice, and miR-133a-3p inhibitor accelerated osteogenic differentiation in BMSCs. SP1 directly targeted miR-133a-3p, and MAPK3 was the downstream mRNA of miR-133a-3p. Mechanically, SP1 accelerated osteogenic differentiation in BMSCs via transcriptional mediation of the miR-133a-3p/MAPK3 axis. CONCLUSION: SP1 regulates osteogenic differentiation by mediating the miR-133a-3p/MAPK3 axis, which would shed new light on strategies for treating senile OP.


Assuntos
Diferenciação Celular , Células-Tronco Mesenquimais , MicroRNAs , Proteína Quinase 3 Ativada por Mitógeno , Osteogênese , Osteoporose , Fator de Transcrição Sp1 , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Osteogênese/genética , Osteogênese/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteoporose/genética , Osteoporose/patologia , Osteoporose/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Camundongos Endogâmicos BALB C , Células Cultivadas , Modelos Animais de Doenças , Masculino
17.
Proc Natl Acad Sci U S A ; 121(29): e2401834121, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38976739

RESUMO

Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master TFs may form phase-separated macromolecular condensates to promote super-enhancer (SE) assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA-binding domain is essential for this process. Through Cleavage Under Targets & Release Using Nuclease (CUT&RUN) using antibodies against SP1 and H3K27ac, we found a significant correlation between SP1 enrichment and SE elements, identified the regulator of the G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through SE mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by glycogen synthase kinase J4 (GSK-J4), a demethylase inhibitor. Together, our findings provide evidence that SP1 regulates its target oncogene expression through phase separation and SE mechanisms, thereby promoting LUAD cell progression. This study also revealed an innovative target for LUAD therapies through intervening in SP1-mediated SE formation.


Assuntos
Adenocarcinoma de Pulmão , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Proteínas RGS , Fator de Transcrição Sp1 , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Humanos , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Proteínas RGS/metabolismo , Proteínas RGS/genética , Linhagem Celular Tumoral , Animais , Elementos Facilitadores Genéticos , Progressão da Doença , Camundongos , Separação de Fases
18.
Cancer Biol Med ; 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38907517

RESUMO

OBJECTIVE: Colorectal cancer (CRC) is a prevalent malignant tumor with a high fatality rate. CircPDIA4 has been shown to have a vital role in cancer development by acting as a facilitator. Nevertheless, the impact of the circPDIA4/miR-9-5p/SP1 axis on development of CRC has not been studied. METHODS: Western blot, immunohistochemistry, and reverse transcription-quantitative polymerase chain reaction assays were used to analyze gene expression. The CCK-8 assay was used to assess cell growth. The Transwell assay was used to detect invasion and migration of cells. The luciferase reporter and RNA immunoprecipitation tests were used to determine if miR-9-5p and circPDIA4 (or SP1) bind to one another. An in vivo assay was used to measure tumor growth. RESULTS: It was shown that circPDIA4 expression was greater in CRC cell lines and tissues than healthy cell lines and tissues. CircPDIA4 knockdown prevented the invasion, migration, and proliferation of cells in CRC. Additionally, the combination of circPDIA4 and miR-9-5p was confirmed, as well as miR-9-5p binding to SP1. Rescue experiments also showed that the circPDIA4/miR-9-5p/SP1 axis accelerated the development of CRC. In addition, SP1 combined with the promoter region of circPDIA4 and induced circPDIA4 transcription. CircPDIA4 was shown to facilitate tumor growth in an in vivo assay. CONCLUSIONS: The circPDIA4/miR-9-5p/SP1 feedback loop was shown to aggravate CRC progression. This finding suggests that the ceRNA axis may be a promising biomarker for CRC patient treatment.

19.
Cancer Lett ; 595: 217025, 2024 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-38844063

RESUMO

Despite the confirmed role of LKB1 in suppressing lung cancer progression, its precise effect on cellular senescence is unknown. The aim of this research was to clarify the role and mechanism of LKB1 in restraining telomerase activity in lung adenocarcinoma. The results showed that LKB1 induced cellular senescence and apoptosis either in vitro or in vivo. Overexpression of LKB1 in LKB1-deficient A549 cells led to the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. As a transcription factor, Sp1 mediated TERT inhibition after LKB1 overexpression. LKB1 induced lactate production and inhibited histone H4 (Lys8) and H4 (Lys16) lactylation, which further altered Sp1-related transcriptional activity. The telomerase inhibitor BIBR1532 was beneficial for achieving the optimum curative effect of traditional chemotherapeutic drugs accompanied by the glycolysis inhibitor 2DG. These data reveal a new mechanism by which LKB1 regulates telomerase activity through lactylation-dependent transcriptional inhibition, and therefore, provide new insights into the effects of LKB1-mediated senescence in lung adenocarcinoma. Our research has opened up new possibilities for the creation of new cancer treatments.


Assuntos
Quinases Proteína-Quinases Ativadas por AMP , Adenocarcinoma de Pulmão , Senescência Celular , Histonas , Neoplasias Pulmonares , Proteínas Serina-Treonina Quinases , Fator de Transcrição Sp1 , Telomerase , Animais , Humanos , Camundongos , Células A549 , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Quinases Proteína-Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Nus , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Fator de Transcrição Sp1/metabolismo , Fator de Transcrição Sp1/genética , Telomerase/metabolismo , Telomerase/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Pharmacol Ther ; 260: 108672, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38838821

RESUMO

The antitumor antibiotic mithramycin A (MTA) binds to G/C-rich DNA sequences in the presence of dications. MTA inhibits transcription regulated by the Sp1 transcription factor, often enhanced during tumor development. It shows antitumor activity, but its clinical use was discontinued due to toxic side effects. However, recent observations have led to its use being reconsidered. The MTA biosynthetic pathways have been modified to produce mithramycin analogs (mithralogs) that encompass lower toxicity and improved pharmacological activity. Some mithralogs reduce gene expression in human ovarian and prostate tumors, among other types of cancer. They down-regulate gene expression in various cellular processes, including Sp1-responsive genes that control tumor development. Moreover, MTA and several mithralogs, such as EC-8042 (DIG-MSK) and EC-8105, effectively treat Ewing sarcoma by inhibiting transcription controlled by the oncogenic EWS-FLI1 transcription factor.


Assuntos
Neoplasias , Plicamicina , Humanos , Plicamicina/análogos & derivados , Plicamicina/farmacologia , Plicamicina/uso terapêutico , Animais , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
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