R1 regulates prostate tumor growth and progression by transcriptional suppression of the E3 ligase HuwE1 to stabilize c-Myc

Tzu Ping Lin, Jingjing Li, Qinlong Li, Xiangyan Li, Chunyan Liu, Ni Zeng, Jen Ming Huang, Gina Chia Yi Chu, Chi Hung Lin, Haiyen E. Zhau, Leland W.K. Chung, Boyang Jason Wu*, Jean C. Shih

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Prostate cancer is a prevalent public health problem, especially because noncutaneous advanced malignant forms significantly affect the lifespan and quality of life of men worldwide. New therapeutic targets and approaches are urgently needed. The current study reports elevated expression of R1 (CDCA7L/RAM2/JPO2), a c-Myc–interacting protein and transcription factor, in human prostate cancer tissue specimens. In a clinical cohort, high R1 expression is associated with disease recurrence and decreased patient survival. Overexpression and knockdown of R1 in human prostate cancer cells indicate that R1 induces cell proliferation and colony formation. Moreover, silencing R1 dramatically reduces the growth of prostate tumor xenografts in mice. Mechanistically, R1 increases c-Myc protein stability by inhibiting ubiquitination and proteolysis through transcriptional suppression of HUWE1, a c-Myc–targeting E3 ligase, via direct interaction with a binding element in the promoter. Moreover, transcriptional repression is supported by a negative coexpression correlation between R1 and HUWE1 in a prostate cancer clinical dataset. Collectively, these findings, for the first time, characterize the contribution of R1 to prostate cancer pathogenesis. Implications: These findings provide evidence that R1 is a novel regulator of prostate tumor growth by stabilizing c-Myc protein, meriting further investigation of its therapeutic and prognostic potential.

Original languageEnglish
Pages (from-to)1940-1951
Number of pages12
JournalMolecular Cancer Research
Volume16
Issue number12
DOIs
StatePublished - 1 Dec 2018

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