CREPT/RPRD1B promotes tumorigenesis through STAT3-driven gene transcription in a p300-dependent manner.

Affiliation

Zhai W(#)(1)(2), Ye X(#)(3), Wang Y(1), Feng Y(1), Wang Y(1), Lin Y(1)(2), Ding L(1), Yang L(1), Wang X(4), Kuang Y(4), Fu X(5), Eugene Chin Y(6), Jia B(4), Zhu B(7), Ren F(8), Chang Z(9).
Author information:
(1)State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China.
(2)Tsinghua-Peking Joint Center for Life Sciences, School of Life Science, Tsinghua University, Beijing, China.
(3)Urology and Lithotripsy Center, Peking University People's Hospital, Beijing, China.
(4)Department of General Surgery, Chinese PLA General Hospital, Beijing, China.
(5)Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Beijing, China.
(6)Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
(7)State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China. [Email]
(8)State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China. [Email]
(9)State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China. [Email]
(#)Contributed equally

Abstract

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) has been shown to upregulate gene transcription during tumorigenesis. However, how STAT3 initiates transcription remains to be exploited. This study is to reveal the role of CREPT (cell cycle-related and elevated-expression protein in tumours, or RPRD1B) in promoting STAT3 transcriptional activity. METHODS: BALB/c nude mice, CREPT overexpression or deletion cells were employed for the assay of tumour formation, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing. RESULTS: We demonstrate that CREPT, a recently identified oncoprotein, enhances STAT3 transcriptional activity to promote tumorigenesis. CREPT expression is positively correlated with activation of STAT3 signalling in tumours. Deletion of CREPT led to a decrease, but overexpression of CREPT resulted in an increase, in STAT3-initiated tumour cell proliferation, colony formation and tumour growth. Mechanistically, CREPT interacts with phosphorylated STAT3 (p-STAT3) and facilitates p-STAT3 to recruit p300 to occupy at the promoters of STAT3-targeted genes. Therefore, CREPT and STAT3 coordinately facilitate p300-mediated acetylation of histone 3 (H3K18ac and H3K27ac), further augmenting RNA polymerase II recruitment. Accordingly, depletion of p300 abolished CREPT-enhanced STAT3 transcriptional activity. CONCLUSIONS: We propose that CREPT is a co-activator of STAT3 for recruiting p300. Our study provides an alternative strategy for the therapy of cancers related to STAT3.