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

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.

IRAK2 contributes to triple-negative breast cancer growth via NF-κB, ERK and stress-related signaling pathways

“…Transcriptome analysis of BCSC1, BCSC3 and MDA-MB-468 revealed that genes downregulated by IRAK2 knockdown are involved in proliferation, self-renewal capacity, cell cycle dysregulation, apoptosis and cell survival, often involving ERK, STAT3, AKT pathways, con rming our in vitro and in vivo data [35][36][37]. Moreover, the transcriptome analysis displayed that IRAK2 downregulation affects pathways involved in cellular metabolic processes, accordant with the recent discovery of IRAK2 involvement in pancreatic cancer metabolic reprogramming through NF-κB signaling [38].…”

Tex10 interacts with STAT3 to regulate hepatocellular carcinoma growth and metastasis

“…Acetylated STAT3 may recruit p300 to the target promoter for histone acetylation. 18 However, our results indicate that a Tex10 deficiency hardly attenuated the histone acetylation marker H3K27ac that flanks the STAT3 binding region; thus, it is unclear if Tex10 promotes the STAT3/ p300 complex to acetylate histone 3, and this will require further study.…”

“…In HepG2‐Tex10 and Huh7‐Tex10 cells, STAT3 acetylation was enhanced (Figure 7A–C). In addition, studies have suggested that acetylated STAT3 may recruit p300 to the target promoter for histone acetylation 18 . A ChIP assay using an Anti‐H3K27ac antibody was performed.…”

“…In HCCLM3 cells, Tex10 had no effect on H3K27 acetylation, flanking the STAT3 binding region (Figure 7D). In cytokine‐induced STAT3 acetylation, p300/CREB‐binding protein acts as a coactivator 18,19 . To examine if Tex10 regulates p300‐mediated acetylation of STAT3, Huh7 cells that were cotransfected with Tex10 and p300 were evaluated and shown to have an increased STAT3 acetylation relative to their independent presence (Figure 7E,G), while acetylation levels were lower in the shTex10 and p300 cotransfected group (Figure 7F,G).…”

“…In addition, studies have suggested that acetylated STAT3 may recruit p300 to the target promoter for histone acetylation. 18 A ChIP assay using an Anti-H3K27ac antibody was performed. In HCCLM3 cells, Tex10 had no effect on H3K27 acetylation, flanking the STAT3 binding region (Figure 7D).…”