Deubiquitinating enzyme USP22 positively regulates c‐Myc stability and tumorigenic activity in mammalian and breast cancer cells

Abstract

The proto-oncogene c-Myc has a pivotal function in growth control, differentiation, and apoptosis and is frequently affected in human cancer, including breast cancer. Ubiquitin-specific protease 22 (USP22), a member of the USP family of deubiquitinating enzymes (DUBs), mediates deubiquitination of target proteins, including histone H2B and H2A, telomeric repeat binding factor 1, and cyclin B1. USP22 is also a component of the mammalian SAGA transcriptional co-activating complex. In this study, we explored the functional role of USP22 in modulating c-Myc stability and its physiological relevance in breast cancer progression. We found that USP22 promotes deubiquitination of c-Myc in several breast cancer cell lines, resulting in increased levels of c-Myc. Consistent with this, USP22 knockdown reduces c-Myc levels. Furthermore, overexpression of USP22 stimulates breast cancer cell growth and colony formation, and increases c-Myc tumorigenic activity. In conclusion, the present study reveals that USP22 in breast cancer cell lines increases c-Myc stability through c-Myc deubiquitination, which is closely correlated with breast cancer progression.

Retracted: Effects of microRNA‐494 on proliferation, migration, invasion, and apoptosis of medulloblastoma cells by mediating c‐myc through the p38 MAPK signaling pathway

“…Initially, it was found that c‐myc gene was the target gene of miR‐494, and that increased miR‐494 expression and decreased c‐myc expression were observed in the miR‐494 mimics group, indicating that the upregulation of miR‐494 and downregulation of c‐myc resulted in the inhibition in the growth of MB. Proto‐oncogene c‐Myc regulates the balance between cell proliferation and cell death by mediating the transcriptional activity of target genes including metabolic enzymes and cell‐cycle regulators . Although there is a high expression of c‐myc in tumors, c‐myc gene amplification does not occur, whereas MBs are often associated with c‐myc amplification and are characterized by a difficult overall prognosis .…”

MYC Deregulation in Primary Human Cancers

“…Several deubiquitinases have been reported to work in opposition to FBXW7 and stabilize MYC, namely ubiquitin specific protease 28 (USP28), USP36, and USP37 [137,138]. More recently, USP22 has also been reported to regulate MYC stability, however it is unknown whether this is in opposition to turnover mediated by FBXW7 [139]. In accordance with MYC’s oncogenic activity, many of these MYC regulators have been characterized either as oncogenes, such as USP28 [140], or tumor suppressors, for example FBXW7 [141].…”

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

“…An alternative strategy to enhance the activity of E3s that target MYC for degradation is to target MYC deubiquinating enzymes (DUBs). DUBs that deubiquitinate and stabilize MYC family proteins include USP7, USP13, USP22, USP28, USP36, and USP37 [173][174][175][176][177][178][179]. Inhibition of these DUBs has been reported to attenuate MYC-dependent gene transcription and increase MYC turnover, with inhibition of USP36 resulting in a dramatic decrease in c-MYC expression and induction of cytotoxicity [175].…”