RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination
| Autor: | Kunkun Han, Zubin Zhang, Ying Ren, Gautam Sethi, Biyin Cao, Xiaowen Tang, Chen-yu Mao, Xin Xu, Yujia Xu, Xinliang Mao |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell Survival dexamethasone RNF6 Article 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Glucocorticoid receptor Receptors Glucocorticoid ubiquitin-proteasome pathway glucocorticoid receptor Humans Pharmacology (medical) Cells Cultured Cell Proliferation Pharmacology Gene knockdown Oncogene biology Dose-Response Relationship Drug Molecular Structure Chemistry Cell growth apoptosis Ubiquitination General Medicine Ubiquitin ligase multiple myeloma DNA-Binding Proteins 030104 developmental biology Proteasome Cell culture 030220 oncology & carcinogenesis biology.protein Cancer research Ectopic expression |
| Zdroj: | Acta Pharmacologica Sinica |
| ISSN: | 1745-7254 1671-4083 |
| Popis: | RNF6, a RING-type ubiquitin ligase, has been identified as an oncogene in various cancers but its role in multiple myeloma (MM) remains elusive. In the present study we first showed that the expression levels of RNF6 in MM were significantly elevated compared with the bone marrow cells of healthy donors. Overexpression of RNF6 in LP1 and PRMI-8266 MM cell lines promoted cell proliferation, whereas knockdown of RNF6 led to apoptosis of MM cells. Furthermore, we revealed that RNF6, as a ubiquitin ligase, interacted with glucocorticoid receptor (GR) and induced its K63-linked polyubiquitination. Different from current knowledge, RNF6 increased GR stability at both endogenous and exogenous contexts. Such an action greatly promoted GR transcriptional activity, which was confirmed by luciferase assays and by the increased expression levels of prosurvival genes including Bcl-xL and Mcl-1, two typical downstream genes of the GR pathway. Consistent with these findings, ectopic expression of RNF6 in MM cells conferred resistance to dexamethasone, a typical anti-myeloma agent. In conclusion, we demonstrate that RNF6 promotes MM cell proliferation and survival by inducing atypical polyubiquitination to GR, and RNF6 could be a promising therapeutic target for the treatment of MM. |
| Databáze: | OpenAIRE |
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