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1.
Hum Cell ; 34(2): 588-597, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33400245

ABSTRACT

MAFG-AS1 is an oncogenic lncRNA in multiple types of cancer. However, its role in bladder cancer (BC) remains unclear. The present study aimed to investigate the function of MAFG-AS1 in BC. BC and paired non-tumor tissues were collected. Two BC cell lines HT01197 and HT-1376 were used. Dual luciferase activity assay, RT-qPCR, western blot, CCK-8, transwell invasion assay, and wound healing assay were performed. We found that MAFG-AS1 was significantly up-regulated in BC tissues and predicted a poor survival rate. MAFG-AS1 interacted with miR-125b-5p. However, the expression levels of MAFG­AS1 and miR-125b-5p were not obviously correlated in BC tissues, and MAFG­AS1 and miR-125b-5p did not regulate the expression of each other. Interestingly, we found that SphK1, a downstream target of miR-125b-5p, was negatively correlated with miR-125b-5p, while it was positively correlated with MAFG-AS1 across BC tissues. In addition, overexpression of MAFG­AS1 upregulated the expression of SphK1 in BC cells, and attenuated the inhibitory effects of miR-125b-5p on the expression of SphK1. Functional assays showed that overexpression of MAFG­AS1 promoted BC cell proliferation, migration, and invasion, while its effects were attenuated by overexpression of miR-125b-5p. Moreover, overexpression of miR-125b-5p inhibited BC cell proliferation, migration, and invasion, while its effects were alleviated by overexpression of SphK1. Taken together, our findings demonstrated that MAFG-AS1 has an oncogenic role in BC by regulating the miR-125b-5p/SphK1 axis. MAFG-AS1 might serve as a good diagnostic marker and a potential therapeutic target of BC.


Subject(s)
Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic/genetics , MafG Transcription Factor/physiology , MicroRNAs/genetics , MicroRNAs/metabolism , Neoplasm Invasiveness/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , Phosphotransferases (Alcohol Group Acceptor)/metabolism , RNA, Long Noncoding/physiology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Adult , Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Female , Humans , Male , Middle Aged , Molecular Targeted Therapy , Urinary Bladder Neoplasms/diagnosis
2.
Aging (Albany NY) ; 12(20): 20658-20683, 2020 10 24.
Article in English | MEDLINE | ID: mdl-33098638

ABSTRACT

Hormone receptor-positive breast cancer accounts for around 75% of breast cancers. The estrogen receptor pathway promotes tumor progression and endocrine resistance. Recently, the cross-talk between the ER signaling pathway and cell cycle regulation has been identified. It is necessary to determine the underlying molecular mechanisms involved in the ER signaling pathway and find new target genes for prognosis and drug resistance in ER+ breast cancer. In this study, lncRNA MAFG-AS1 was shown to be up-regulated and associated with poor prognosis in ER+ breast cancer. Functionally, down-regulation of MAFG-AS1 could inhibit cell proliferation and promote apoptosis. In addition, MAFG-AS1 which contained an estrogen-responsive element could promote CDK2 expression by sponging miR-339-5p. Subsequently, MAFG-AS1 and CDK2 were found to be up-regulated in tamoxifen-resistant MCF-7 cells. Cross-talk between the ER signaling pathway and cell cycle conducted by MAFG-AS1 and CDK2 could promote tamoxifen resistance. In conclusion, our study indicated that estrogen-responsive lncRNA MAFG-AS1 up-regulated CDK2 by sponging miR-339-5p, which promoted ER+ breast cancer proliferation. Cross-talk between the ER signaling pathway and cell cycle suggested that lncRNA MAFG-AS1 is a potential biomarker and therapeutic target in ER+ breast cancer. CDK2 inhibitors may be applied to endocrine resistance therapy.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Cyclin-Dependent Kinase 2/physiology , Drug Resistance, Neoplasm , MafG Transcription Factor/physiology , MicroRNAs/physiology , RNA, Long Noncoding , Receptor Cross-Talk , Receptors, Estrogen/physiology , Repressor Proteins/physiology , Signal Transduction , Tamoxifen/therapeutic use , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cyclin-Dependent Kinase 2/genetics , Disease Progression , Drug Resistance, Neoplasm/genetics , Female , Humans , MafG Transcription Factor/genetics , MicroRNAs/genetics , Middle Aged , Repressor Proteins/genetics
3.
Transl Res ; 200: 1-17, 2018 10.
Article in English | MEDLINE | ID: mdl-30053382

ABSTRACT

Adjuvant chemotherapy for solid tumors based on platinum-derived compounds such as cisplatin is the treatment of choice in most cases. Cisplatin triggers signaling pathways that lead to cell death, but it also induces changes in tumor cells that modify the therapeutic response, thereby leading to cisplatin resistance. We have recently reported that microRNA-7 is silenced by DNA methylation and is involved in the resistance to platinum in cancer cells through the action of the musculoaponeurotic fibrosarcoma oncogene family, protein G (MAFG). In the present study, we first confirm the miR-7 epigenetic regulation of MAFG in 44 normal- and/or tumor-paired samples in non-small-cell lung cancer (NSCLC). We also provide translational evidence of the role of MAFG and the clinical outcome in NSCLC by the interrogation of two extensive in silico databases of 2019 patients. Moreover, we propose that MAFG-mediated resistance could be conferred due to lower reactive oxygen species production after cisplatin exposure. We developed specifically selected aptamers against MAFG, with high sensitivity to detect the protein at a nuclear level probed by aptacytochemistry and histochemistry analyses. The inhibition of MAFG activity through the action of the specific aptamer apMAFG6F increased the levels of reactive oxygen species production and the sensitivity to cisplatin. We report first the specific nuclear identification of MAFG as a novel detection method for diagnosis in NSCLC, and then we report that MAFG modulates the redox response and confers cell protection against free radicals generated after platinum administration, thus also being a promising therapeutic target.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/therapeutic use , Drug Resistance, Neoplasm/drug effects , Lung Neoplasms/drug therapy , MafG Transcription Factor/antagonists & inhibitors , Repressor Proteins/antagonists & inhibitors , Aptamers, Nucleotide/chemistry , Aptamers, Nucleotide/genetics , Aptamers, Nucleotide/pharmacology , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cloning, Molecular , DNA Methylation , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/physiology , Epigenesis, Genetic/genetics , Gene Expression , Gene Silencing , HEK293 Cells , Humans , Lung Neoplasms/genetics , MafG Transcription Factor/genetics , MafG Transcription Factor/physiology , MicroRNAs/genetics , MicroRNAs/physiology , Oxidation-Reduction , Prognosis , Reactive Oxygen Species/metabolism , Repressor Proteins/genetics , Repressor Proteins/physiology , Sequence Analysis, DNA , Transfection
4.
Gene ; 586(2): 197-205, 2016 Jul 25.
Article in English | MEDLINE | ID: mdl-27058431

ABSTRACT

The small Maf proteins (sMafs) are basic region leucine zipper (bZIP)-type transcription factors. The basic region of the Maf family is unique among the bZIP factors, and it contributes to the distinct DNA-binding mode of this class of proteins. MafF, MafG and MafK are the three vertebrate sMafs, and no functional differences have been observed among them in terms of their bZIP structures. sMafs form homodimers by themselves, and they form heterodimers with cap 'n' collar (CNC) proteins (p45 NF-E2, Nrf1, Nrf2, and Nrf3) and also with Bach proteins (Bach1 and Bach2). Because CNC and Bach proteins cannot bind to DNA as monomers, sMafs are indispensable partners that are required by CNC and Bach proteins to exert their functions. sMafs lack the transcriptional activation domain; hence, their homodimers act as transcriptional repressors. In contrast, sMafs participate in transcriptional activation or repression depending on their heterodimeric partner molecules and context. Mouse genetic analyses have revealed that various biological pathways are under the regulation of CNC-sMaf heterodimers. In this review, we summarize the history and current progress of sMaf studies in relation to their partners.


Subject(s)
MafF Transcription Factor/physiology , MafG Transcription Factor/physiology , MafK Transcription Factor/physiology , Animals , DNA/metabolism , DNA-Binding Proteins , Disease , History, 20th Century , History, 21st Century , Humans , MafF Transcription Factor/chemistry , MafF Transcription Factor/genetics , MafF Transcription Factor/history , MafG Transcription Factor/chemistry , MafG Transcription Factor/genetics , MafG Transcription Factor/history , MafK Transcription Factor/chemistry , MafK Transcription Factor/genetics , MafK Transcription Factor/history , Mice , Nuclear Proteins/genetics , Repressor Proteins/genetics
5.
Proc Natl Acad Sci U S A ; 113(5): 1250-5, 2016 Feb 02.
Article in English | MEDLINE | ID: mdl-26787892

ABSTRACT

During cancer development, it is well established that many genes, including tumor suppressor genes, are hypermethylated and transcriptionally repressed, a phenomenon referred to as epigenetic silencing. In general, the factors involved in, and the mechanistic basis of, epigenetic silencing during cancer development are not well understood. We have recently described an epigenetic silencing pathway, directed by the oncogenic B-Raf proto-oncogene (BRAF) variant BRAF(V600E), that mediates widespread epigenetic silencing in colorectal cancer (CRC). Notably, the BRAF(V600E) mutation is also present in 50-70% of melanomas. Here, we show that the same pathway we identified in CRC also directs epigenetic silencing of a similar set of genes in BRAF-positive melanoma. In both CRC and melanoma, BRAF(V600E) promotes epigenetic silencing through up-regulation of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG), a transcriptional repressor with sequence-specific DNA-binding activity. The elevated concentration of MAFG drives DNA binding on the promoter. Promoter-bound MAFG recruits a set of corepressors that includes its heterodimeric partner BTB and CNC homology 1, basic leucine zipper transcription factor 1 (BACH1), the chromatin remodeling factor chromodomain helicase DNA-binding protein 8 (CHD8), and the DNA methyltransferase DNMT3B, resulting in hypermethylation and transcriptional silencing. Our results reveal a common BRAF(V600E)-directed transcriptional regulatory pathway that mediates epigenetic silencing in unrelated solid tumors and provide strong support for an instructive model of oncoprotein-directed epigenetic silencing.


Subject(s)
Colorectal Neoplasms/genetics , Epigenesis, Genetic/physiology , Gene Silencing , MafG Transcription Factor/physiology , Melanoma/genetics , Proto-Oncogene Proteins B-raf/physiology , Repressor Proteins/physiology , Cell Line, Tumor , DNA Methylation , Humans , Proto-Oncogene Mas , Up-Regulation
6.
Mol Cell Biol ; 32(4): 808-16, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22158967

ABSTRACT

Embryogenesis is a period during which cells are exposed to dynamic changes of various intracellular and extracellular stresses. Oxidative stress response genes are regulated by heterodimers composed of Cap'n'Collar (CNC) and small Maf proteins (small Mafs) that bind to antioxidant response elements (ARE). Whereas CNC factors have been shown to contribute to the expression of ARE-dependent cytoprotective genes during embryogenesis, the specific contribution of small Maf proteins to such gene regulation remains to be fully examined. To delineate the small Maf function in vivo, in this study we examined mice lacking all three small Mafs (MafF, MafG, and MafK). The small Maf triple-knockout mice developed normally until embryonic day 9.5 (E9.5). Thereafter, however, the triple-knockout embryos showed severe growth retardation and liver hypoplasia, and the embryos died around E13.5. ARE-dependent cytoprotective genes were expressed normally in E10.5 triple-knockout embryos, but the expression was significantly reduced in the livers of E13.5 mutant embryos. Importantly, the embryonic lethality could be completely rescued by transgenic expression of exogenous MafG under MafG gene regulatory control. These results thus demonstrate that small Maf proteins are indispensable for embryonic development after E9.5, especially for liver development, but early embryonic development does not require small Mafs.


Subject(s)
Liver/embryology , MafF Transcription Factor/deficiency , MafG Transcription Factor/deficiency , MafK Transcription Factor/deficiency , Nuclear Proteins/deficiency , Repressor Proteins/deficiency , Animals , Apoptosis , Base Sequence , DNA Primers/genetics , DNA-Binding Proteins , Female , Fetal Death , Gene Expression Regulation, Developmental , Gestational Age , Liver/metabolism , MafF Transcription Factor/genetics , MafF Transcription Factor/physiology , MafG Transcription Factor/genetics , MafG Transcription Factor/physiology , MafK Transcription Factor/genetics , MafK Transcription Factor/physiology , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Knockout , Nuclear Proteins/genetics , Nuclear Proteins/physiology , Pregnancy , Repressor Proteins/genetics , Repressor Proteins/physiology
7.
Exp Hematol ; 38(12): 1251-60, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20813153

ABSTRACT

OBJECTIVE: MafG is the small subunit of the transcription factor NF-E2 that controls terminal megakaryocyte maturation and platelet release. Studies were conducted to evaluate the intrinsic and extrinsic effects of mafG deficiency on bone marrow engraftment kinetics. MATERIALS AND METHODS: We used mafG knockout mice either as donors or recipients in bone marrow transplantations with wild-type mice and compared the engraftment kinetics to transplantations using wild-type donors and recipients. We measured peripheral cell counts, the presence of circulating donor-derived cells by flow cytometry, changes in the cellularity of the bone marrow and splenic weight on day 5, 7, 14, and 1 month post-transplantation. RESULTS: Compared to wild-type recipients, mafG recipients had delayed platelet and leukocyte recovery and lower spleen weight at early time points after transplantation. Intrinsic effects: When mafG-deficient bone marrow served as donor source, we observed more rapid recovery of bone marrow cellularity and increased splenic hematopoiesis. The finding of increased short-term hematopoietic stem cells and progenitors in the mafG-deficient bone marrow could explain the accelerated hematopoietic recovery after transplantation. Furthermore, the expression of Bach 2, which can form a heterodimer with mafG protein, was found to be greatly reduced, while Notch 1 expression was increased in mafG-deficient mice. Extrinsic effects: When mafG-deficient mice were transplant recipients, there were delays in recovery of normal levels of marrow and splenic hematopoiesis as well as circulating leukocytes and platelets. CONCLUSIONS: Our study demonstrates that mafG expression has intrinsic and extrinsic effects on hematopoietic engraftment following bone marrow transplantation.


Subject(s)
Bone Marrow Transplantation , Hematopoiesis , MafG Transcription Factor/physiology , Repressor Proteins/physiology , Animals , Basic-Leucine Zipper Transcription Factors/analysis , Hematopoietic Stem Cells/cytology , Leukocyte Count , MafG Transcription Factor/deficiency , Megakaryocytes/physiology , Mice , Mice, Knockout , Platelet Count , Receptor, Notch1/analysis , Repressor Proteins/deficiency , Spleen/cytology
8.
Hepatology ; 51(4): 1291-301, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20146260

ABSTRACT

UNLABELLED: We previously showed that hepatic expression of glutathione (GSH) synthetic enzymes and GSH levels fell 2 weeks after bile duct ligation (BDL) in mice. This correlated with a switch in nuclear anti-oxidant response element (ARE) binding activity from nuclear factor erythroid 2-related factor 2 (Nrf2) to c-avian musculoaponeurotic fibrosarcoma (c-Maf)/V-maf musculoaponeurotic fibrosarcoma oncogene homolog G (MafG). Our current aims were to examine whether the switch in ARE binding activity from Nrf2 to Mafs is responsible for decreased expression of GSH synthetic enzymes and the outcome of blocking this switch. Huh7 cells treated with lithocholic acid (LCA) exhibited a similar pattern of change in GSH synthetic enzyme expression as BDL mice. Nuclear protein levels of Nrf2 fell at 20 hours after LCA treatment, whereas c-Maf and MafG remained persistently induced. These changes translated to ARE nuclear binding activity. Knockdown of c-Maf or MafG individually blunted the LCA-induced decrease in Nrf2 ARE binding and increased ARE-dependent promoter activity, whereas combined knockdown was more effective. Knockdown of c-Maf or MafG individually increased the expression of GSH synthetic enzymes and raised GSH levels, and combined knockdown exerted an additive effect. Ursodeoxycholic acid (UDCA) or S-adenosylmethionine (SAMe) prevented the LCA-induced decrease in expression of GSH synthetic enzymes and promoter activity and prevented the increase in MafG and c-Maf levels. In vivo knockdown of the Maf genes protected against the decrease in GSH enzyme expression, GSH level, and liver injury after BDL. CONCLUSION: Toxic bile acid induces a switch from Nrf2 to c-Maf/MafG ARE nuclear binding, which leads to decreased expression of GSH synthetic enzymes and GSH levels and contributes to liver injury during BDL. UDCA and SAMe treatment targets this switch.


Subject(s)
Cholestasis/etiology , Glutathione/biosynthesis , Lithocholic Acid/toxicity , MafG Transcription Factor/physiology , Repressor Proteins/physiology , Animals , Cell Line, Tumor , Glutamate-Cysteine Ligase/genetics , Humans , MafK Transcription Factor/physiology , Male , Mice , Mice, Inbred C57BL , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/physiology , Promoter Regions, Genetic , Response Elements/physiology , S-Adenosylmethionine/pharmacology , Ursodeoxycholic Acid/pharmacology
9.
FEBS Lett ; 582(16): 2357-64, 2008 Jul 09.
Article in English | MEDLINE | ID: mdl-18538669

ABSTRACT

We identified MafG as a protein that interacts with HIF-1alpha, a key factor in hypoxic response, using the yeast two-hybrid system. Interaction between MafG and HIF-1alpha was confirmed by surface plasmon resonance and by translocation to the nucleolus with the NoLS signal. A knockdown of MafG reduced erythropoietin (EPO) mRNA levels as well as luciferase reporter activity with the hypoxia response element. The knockdown of MafG did not change total HIF-1alpha protein, but reduced the accumulation of HIF-1alpha in the nuclei. These results suggest that MafG regulates the hypoxic response of cells by detaining HIF-1alpha in the nuclei.


Subject(s)
Cell Nucleus/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , MafG Transcription Factor/physiology , Repressor Proteins/physiology , Cell Hypoxia , Cell Line, Tumor , Genes, Reporter , Humans , MafG Transcription Factor/antagonists & inhibitors , MafG Transcription Factor/genetics , RNA Interference , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/genetics , Two-Hybrid System Techniques
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