Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monoubiquitylation of histone H2B (H2Bub1) is catalyzed mainly by the RNF20/RNF40 complex and erased by multiple deubiquitylating enzymes (DUBs). H2Bub1 influences many aspects of chromatin function, including transcription regulation and DNA repair. Cancer cells often display reduced levels of H2Bub1, and this reduction may contribute to cancer progression. The let-7 family of microRNAs (miRNAs) comprises multiple members with reported tumor-suppressive features, whose expression is frequently downregulated in cancer. We now report that let-7b and let-7c can positively regulate cellular H2Bub1 levels. Overexpression of let-7b and let-7c in a variety of non-transformed and cancer-derived cell lines results in H2Bub1 elevation. The positive effect of let-7b and let-7c on H2Bub1 levels is achieved through targeting of multiple mRNAs, coding for distinct components of the H2B deubiquitylation machinery. Specifically, let-7b and let-7c bind directly and inhibit the mRNAs encoding the DUBs USP42 and USP44, and also the mRNA encoding the adapter protein ATXN7L3, which is part of the DUB module of the SAGA complex. RNF20 knockdown (KD) strongly reduces H2Bub1 levels and increases the migration of non-transformed mammary epithelial cells and breast cancer-derived cells. Remarkably, overexpression of let-7b, which partly counteracts the effect of RNF20 KD on H2Bub1 levels, also reverses the pro-migratory effect of RNF20 KD. Likewise, ATXN7L3 KD also increases H2Bub1 levels and reduces cell migration, and this anti-migratory effect is abolished by simultaneous KD of RNF20. Together, our findings uncover a novel function of let-7 miRNAs as regulators of H2B ubiquitylation, suggesting an additional mechanism whereby these miRNAs can exert their tumor-suppressive effects.
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PMID:let-7b and let-7c microRNAs promote histone H2B ubiquitylation and inhibit cell migration by targeting multiple components of the H2B deubiquitylation machinery. 2860 53

Background: Increasing evidence enhanced the recognition of circular RNAs (circRNAs) implicated in cancer progression. CircRNA_0085616 (circ_0085616) is a novel circRNA with high expression in cervical cancer (CC); its function and action mechanism are explored during this study. Methods: The measurement of circ_0085616, microRNA-503-5p (miR-503-5p), and Ataxin-7L3 (ATXN7L3) was performed via quantitative real-time polymerase chain reaction. Next, 3-(4,5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) and colony formation assays were implemented to analyze the proliferative ability. Cell metastasis was evaluated by using transwell migration and invasion assays. Glycolysis was analyzed by using glucose consumption, lactate and adenosine triphosphate production. Western blot was employed for protein analysis. The target binding was performed by dual-luciferase reporter assay and RNA immunoprecipitation assay. An animal experiment in vivo was conducted by xenografts. Results: Circ_0085616 was heightened and its downregulation blocked cellular proliferation, metastasis, and glycolysis in CC. Then, we found that circ_0085616 had a sponge effect on miR-503-5p and the miR-503-5p inhibitor could ameliorate the effects of circ_0085616 knockdown on CC cells. In addition, miR-503-5p directly targeted ATXN7L3 to obstruct CC cell proliferation, metastasis, and glycolytic process. Further, circ_0085616 could enhance ATXN7L3 by sequestering miR-503-5p, and the miR-503-5p/ATXN7L3 axis was also responsible for circ_0085616 on promoting CC tumorigenesis in vivo. Conclusion: It was obvious that circ_0085616 facilitated the carcinogenic effect on CC via the activation of ATXN7L3 by sponging miR-503-5p. Our study may be likely to provide a novel molecular target for CC therapy.
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PMID:Identification of circ_0085616 as an Upregulated and Oncogenic Circular RNA in Cervical Cancer Via the miR-503-5p-Mediated ATXN7L3 Activation. 3309 6