CREPT is required for murine stem cell maintenance during intestinal regeneration

Liu, Yang; Yang, Han–Soeb; Chu, Yunxiang; Song, Yunhao; Ding, Lidan; Zhu, Bingtao; Zhai, Wanli; Wang, Xuning; Kuang, Yanshen; Ren, Fei; Jia, Baoqing; Wu, Wei; Ye, Xiongjun; Wang, Yinyin; Chen, Zhijie

doi:10.1038/s41467-020-20636-9

Cited by 15 publications

(9 citation statements)

References 62 publications

(46 reference statements)

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“…We previously identified a gene CREPT (cell cycle-related and elevated-expression protein in tumours, or RPRD1B ) that is highly expressed in varieties of human tumours 35 – 44 and also murine stem cells. 45 CREPT promotes tumorigenesis through upregulation of a set of cell cycle-related genes. A mechanism study revealed that CREPT facilitates the recruitment of RNAPII to the promoter region and blocks its reading through the pol(A) signal in the termination region of the CCND1 gene.…”

Section: Introductionmentioning

confidence: 99%

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

Zhai

Wang

et al. 2021

Br J Cancer

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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.

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Section: Introductionmentioning

confidence: 99%

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

Zhai

Wang

et al. 2021

Br J Cancer

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“…Our work demonstrates that Mex3a activates WNT in ISCs by directly suppressing Klf4. The intestinal phenotypes of Mex3a -deficient mice recapitulate these induced by loss of WNT function 55 , 56 . Thus, it is likely that Mex3a indirectly suppresses PPARγ activity via Klf4-mediated WNT signaling activation in ISCs.…”

Section: Discussionmentioning

confidence: 91%

Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state

Yang¹,

Li²,

Tian³

et al. 2022

Theranostics

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Rationale: Dysregulation of signaling that governs self-renewal and differentiation of intestinal stem cells (ISCs) is a major cause of colorectal cancer (CRC) initiation and progression. Methods: qRT-PCR, western blotting, in situ hybridization, immunohistochemistry and immunofluorescence assays were used to detect the expression levels of MEX3A, KLF4 and E2F3 in CRC tissues. The biological functions of MEX3A were studied using Mex3a knockout (KO) and intestinal epithelium specific conditional knockout (cKO) mice, AOM-DSS mouse colorectal tumor model, Apc floxed mouse tumor model and intestinal and tumor organoids. Transcriptomic RNA sequencing (RNA-seq), RNA crosslinking immunoprecipitation (CLIP) and luciferase reporter assays were performed to explore the molecular mechanisms of MEX3A. Results: RNA-binding protein MEX3A, a specific ISC marker gene, becomes ectopically upregulated upon CRC and its levels negatively correlate with patient survival prognosis. MEX3A functions as an oncoprotein that retains cancer cells in undifferentiated and proliferative status and it enhances their radioresistance to DNA damage. Mechanistically, a rate limiting factor of cellular proliferation E2F3 induces MEX3A, which in turn activates WNT pathway by directly suppressing expression of its pro-differentiation transcription factor KLF4. Knockdown of MEX3A with siRNA or addition of KLF4 agonist significantly suppressed tumor growth both by increasing differentiation status of cancer cells and by suppressing their proliferation. Conclusions: It identifies E2F3-MEX3A-KLF4 axis as an essential coordinator of cancer stem cell self-renewal and differentiation, representing a potent new druggable target for cancer differentiation therapy.

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“…no. HY-10295; MedChemExpress) was used to treat RA-FLSs for 1 h at 37°C based on previous studies ( 28 , 29 ).…”

Section: Methodsmentioning

confidence: 99%

Ubiquitin D promotes the progression of rheumatoid arthritis via activation of the p38 MAPK pathway

et al. 2023

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Ubiquitin D (UBD), a member of the ubiquitin-like modifier family, has been reported to be highly expressed in various types of cancer and its overexpression is positively associated with tumor progression. However, the role and mechanism of UBD in rheumatoid arthritis (RA) remain elusive. In the present study, the gene expression profiles of GSE55457 were downloaded from the Gene Expression Omnibus database to assess differentially expressed genes and perform functional enrichment analyses. UBD was overexpressed by lentivirus transfection. The protein level of UBD, p-p38 and p38 in RA-fibroblast-like synoviocytes (FLSs) were examined by western blotting. Cell Counting Kit-8 and flow cytometry assays were used to detect the functional changes of RA-FLSs transfected with UBD and MAPK inhibitor SB202190. The concentrations of inflammatory factors (IL-2, IL-6, IL-10 and TNF-α) were evaluated using ELISA kits. The results revealed that UBD was overexpressed in RA tissues compared with in the healthy control tissues. Functionally, UBD significantly accelerated the viability and proliferation of RA-FLSs, whereas it inhibited their apoptosis. Furthermore, UBD significantly promoted the secretion of inflammatory factors (IL-2, IL-6, IL-10 and TNF-α). Mechanistically, elevated UBD activated phospohorylated-p38 in RA-FLSs. By contrast, UBD overexpression and treatment with the p38 MAPK inhibitor SB202190 not only partially relieved the UBD-dependent effects on cell viability and proliferation, but also reversed its inhibitory effects on cell apoptosis. Furthermore, SB202190 partially inhibited the effects of UBD overexpression on the enhanced secretion of inflammatory factors. The present study indicated that UBD may mediate the activation of p38 MAPK, thereby facilitating the proliferation of RA-FLSs and ultimately promoting the progression of RA. Therefore, UBD may be considered a potential therapeutic target and a promising prognostic biomarker for RA.

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CREPT is required for murine stem cell maintenance during intestinal regeneration

Cited by 15 publications

References 62 publications

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

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

Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state

Ubiquitin D promotes the progression of rheumatoid arthritis via activation of the p38 MAPK pathway

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