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1.
Cell Signal ; 107: 110677, 2023 07.
Article in English | MEDLINE | ID: mdl-37028779

ABSTRACT

RNF31, an atypical E3 ubiquitin ligase of the RING-between-RING protein family, is one of the important components of the linear ubiquitin chain complex LUBAC. It plays a carcinogenic role in a variety of cancers by promoting cell proliferation, invasion and inhibiting apoptosis. However, the specific molecular mechanism by which RNF31 exerts its cancer-promoting effects is still unclear. By analyzing the expression profile of RNF31-depleted cancer cells, we found that loss of RNF31 significantly resulted in the inactivation of the c-Myc pathway. We further showed that RNF31 played an important role in the maintenance of c-Myc protein levels in cancer cells by extending the half-life of c-Myc protein and reducing its ubiquitination. c-Myc protein levels are tightly regulated by the ubiquitin proteasome, in which the E3 ligase FBXO32 is required to mediate its ubiquitin-dependent degradation. We found that RNF31 inhibited the transcription of FBXO32 through EZH2-mediated trimethylation of histone H3K27 in the FBXO32 promoter region, leading to the stabilization and activation of c-Myc protein. Under this circumstance, the expression of FBXO32 was significantly increased in RNF31-deficient cells, promoting the degradation of c-Myc protein, inhibiting cell proliferation and invasion, increasing cell apoptosis, and ultimately blocking the progression of tumors. Consistent with these results, the reduced malignancy phenotype caused by RNF31 deficiency could be partially reversed by overexpression of c-Myc or further knockdown of FBXO32. Together, our results reveal a key association between RNF31 and epigenetic inactivation of FBXO32 in cancer cells, and suggest that RNF31 may be a promising target for cancer therapy.


Subject(s)
Neoplasms , Ubiquitin , Humans , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Neoplasms/genetics , Epigenesis, Genetic , Muscle Proteins/metabolism , SKP Cullin F-Box Protein Ligases/genetics
2.
Anticancer Drugs ; 34(7): 803-815, 2023 08 01.
Article in English | MEDLINE | ID: mdl-36729405

ABSTRACT

The triple-negative breast cancer (TNBC) subtype is the most aggressive type of breast cancer with a low survival prognosis and high recurrence rate. There is currently no effective treatment to improve it. In this work, we explored the effect of a synthetic compound named WXJ-103 on several aspects of TNBC biology. The human breast cancer cell lines MDA-MB-231 and MCF-7 were used in the experiments, and the cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, and the cell migration and invasion abilities were detected by wound healing assay and Transwell invasion assay. Cell cycle and apoptosis experiments were analyzed by flow cytometry, and protein levels related to cyclin-dependent kinase (CDK) 4/6-cyclin D-Rb-E2F pathway were analyzed by western blotting. Then, in-vivo experiments were performed to determine the clinical significance and functional role of WXJ-103. The results show that WXJ-103 can inhibit the adhesion, proliferation, migration, and invasion of TNBC cells, and can arrest the cell cycle in G1 phase. The levels of CDK4/6-cyclin D-Rb-E2F pathway-related proteins such as CDK6 and pRb decreased in a dose-dependent manner. Therefore, the antitumor activity of WXJ-103 may depend on the inhibition of CDK4/6-cyclin D1-Rb-E2F pathway. This research shows that WXJ-103 may be a new promising antitumor drug, which can play an antitumor effect on TNBC and provide new ideas for the treatment of TNBC.


Subject(s)
Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/pathology , Cell Proliferation , Aminopyridines/pharmacology , Aminopyridines/therapeutic use , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 4/therapeutic use , Purines/pharmacology , Cell Line, Tumor
3.
Cell Death Dis ; 14(2): 83, 2023 02 04.
Article in English | MEDLINE | ID: mdl-36739418

ABSTRACT

SEMA6A is a multifunctional transmembrane semaphorin protein that participates in various cellular processes, including axon guidance, cell migration, and cancer progression. However, the role of SEMA6A in clear cell renal cell carcinoma (ccRCC) is unclear. Based on high-throughput sequencing data, here we report that SEMA6A is a novel target gene of the VHL-HIF-2α axis and overexpressed in ccRCC. Chromatin immunoprecipitation and reporter assays revealed that HIF-2α directly activated SEMA6A transcription in hypoxic ccRCC cells. Wnt/ß-catenin pathway activation is correlated with the expression of SEMA6A in ccRCC; the latter physically interacted with SEC62 and promoted ccRCC progression through SEC62-dependent ß-catenin stabilization and activation. Depletion of SEMA6A impaired HIF-2α-induced Wnt/ß-catenin pathway activation and led to defective ccRCC cell proliferation both in vitro and in vivo. SEMA6A overexpression promoted the malignant phenotypes of ccRCC, which was reversed by SEC62 depletion. Collectively, this study revealed a potential role for VHL-HIF-2α-SEMA6A-SEC62 axis in the activation of Wnt/ß-catenin pathway. Thus, SEMA6A may act as a potential therapeutic target, especially in VHL-deficient ccRCC.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Semaphorins , Humans , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , beta Catenin/genetics , beta Catenin/metabolism , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kidney Neoplasms/metabolism , Semaphorins/genetics , Semaphorins/metabolism , Up-Regulation , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Von Hippel-Lindau Tumor Suppressor Protein/metabolism
4.
Bioorg Med Chem Lett ; 81: 129144, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36681201

ABSTRACT

BCR-ABL1 kinase is a key driver of the pathophysiology of chronic myeloid leukemia (CML). Current treatments need to broaden the chemical diversity of BCR-ABL1 kinase inhibitors to overcome drug resistance. We designed and synthesized a series of aromatic amide derivatives based on several generations of BCR-ABL1 kinase inhibitors. Biological studies showed that compared with Imatinib, these compounds showed significant proliferation inhibitory activities of HL-60 and K562 in cell activity assay. Compounds 4g and 4j exhibited significant anti-tumor activity against the K562 cells with IC50 values of 6.03 ± 0.49 µM and 5.66 ± 2.06 µM respectively. Compounds 4g and 4j, as potential BCR-ABL1 inhibitors, inhibit the phosphorylation of ABL1 and CRKL in a dose-dependent manner. Therefore, compounds 4g and 4j can be used as a starting point for further optimization.


Subject(s)
Amides , Fusion Proteins, bcr-abl , Humans , Amides/pharmacology , Drug Resistance, Neoplasm , Protein Kinase Inhibitors/pharmacology , Imatinib Mesylate/pharmacology , K562 Cells , Apoptosis
5.
Biochem Biophys Res Commun ; 587: 139-145, 2022 01 08.
Article in English | MEDLINE | ID: mdl-34872002

ABSTRACT

UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to small lipophilic chemicals and are associated with a wide range of diseases including cancer. The human genome contains 22 UGT genes which could be classified into four families: UGT1, UGT2, UGT3, and UGT8. The UGT8 family contains only one member which utilizes UDP galactose to galactosidate ceramide. Although higher UGT8 mRNA was observed in some types of cancer, its pathological significances remain elusive. Here, by integrating the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Genotype-Tissue Expression (GTEx) databases, we showed that UGT8 was selectively highly expressed in non-small cell lung cancer (NSCLC) and associated with worse prognosis. The transcription factor SOX9 promoted UGT8 expression in NSCLC by recognizing two putative response elements localized on the promoter region of UGT8. Silencing UGT8 impaired glycolysis and reduced the malignancy of NSCLC cells both in vitro and in vivo. On the contrary, inhibition of glycolysis by 2-deoxy-d-glucose (2-DG) significantly impaired the pro-proliferation function of UGT8 in NSCLC cells. In conclusion, our results suggest that UGT8 maintains the malignancy of NSCLC mainly via enhanced glycolysis and provides a promising therapeutic target for NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Ganglioside Galactosyltransferase/genetics , Glycolysis/genetics , Lung Neoplasms/genetics , SOX9 Transcription Factor/genetics , A549 Cells , Animals , Atlases as Topic , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Datasets as Topic , Ganglioside Galactosyltransferase/metabolism , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Mice , Mice, Nude , Neoplasm Invasiveness , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , SOX9 Transcription Factor/antagonists & inhibitors , SOX9 Transcription Factor/metabolism , Signal Transduction , Survival Analysis , Xenograft Model Antitumor Assays
6.
Front Pharmacol ; 13: 1072194, 2022.
Article in English | MEDLINE | ID: mdl-36744210

ABSTRACT

Cyclin-dependent kinases 4 and 6 (CDK4/6) are key regulatory proteins in the cell division and proliferative cycle in humans. They are overactive in many malignant tumors, particularly in triple-negative breast cancer (TNBC). Inhibition of CDK4/6 targets can have anti-tumor effects. Here, we designed and synthesized a novel derivative of Ribociclib that could affect CDK4/6, named WXJ-202. This study aimed to investigate the effects of compound WXJ-202 on proliferation, apoptosis, and cell cycle arrest in human breast cancer cell lines and their molecular mechanisms. We assayed cell viability with methyl thiazolyl tetrazolium (MTT) assay. Clone formation, migration, and invasion ability were assayed by clone formation assay, wound healing assay, and transwell invasion assay. The effect of compound WXJ-202 on apoptosis and cell cycle was detected by flow cytometry analysis. Western blotting was performed to detect the expression of proteins related to the CDK4/6-Rb-E2F pathway. The anti-cancer effects were studied in vivo transplantation tumor models. WXJ-202 was shown to inhibit cell proliferation, colony formation, migration, and invasion, as well as induce apoptosis and cycle arrest in breast cancer cells. The levels of proteins related to the CDK4/6-Rb-E2F pathway, such as CDK4, CDK6, and p-Rb, were decreased. Finally, studies had shown that compound WXJ-202 exhibited significant anti-tumor activity in transplantation tumor models. In this research, the compound WXJ-202 was shown to have better anti-tumor cell proliferative effects and could be used as a potential candidate against TNBC tumors.

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