Dataset Information

CPEB4 Inhibit Cell Proliferation via Upregulating p21 mRNA Stability in Renal Cell Carcinoma.

ABSTRACT: Cytoplasmic polyadenylation element-binding protein 4 (CPEB4) has been reported to be dysregulated in a variety of cancers and seems to play paradoxical roles in different cancers. However, the functional roles of CPEB4 in Renal cell carcinoma (RCC) are still unclear. This study aims to explore the role and underlying mechanism of CPEB4 in RCC. We found that the relative expression level of CPEB4 is down-regulated in RCC tissues and cell lines, and the low CPEB4 expression is correlated with short overall and disease-free survival of RCC patients. CPEB4 significantly inhibits RCC tumor growth both in vivo and in vitro. CPEB4 exerts an anti-tumor effect by increasing p21 mRNA stability and inducing G1 cell cycle arrest in RCC. Our data revealed that CPEB4 is a tumor suppressor gene that restrains cell cycle progression upstream of p21 in RCC. These findings revealed that CPEB4 may become a promising predictive biomarker for prognosis in patients with RCC.

SUBMITTER: Di J

PROVIDER: S-EPMC8716440 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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CPEB4 Inhibit Cell Proliferation via Upregulating p21 mRNA Stability in Renal Cell Carcinoma.

Di Jiehui J Wang Hui H Zhao Zhongjun Z Zhao Guang G Qin Xiaobing X Han Zhengxiang Z Liu Yong Y

Frontiers in cell and developmental biology 20211216

Cytoplasmic polyadenylation element-binding protein 4 (CPEB4) has been reported to be dysregulated in a variety of cancers and seems to play paradoxical roles in different cancers. However, the functional roles of CPEB4 in Renal cell carcinoma (RCC) are still unclear. This study aims to explore the role and underlying mechanism of CPEB4 in RCC. We found that the relative expression level of CPEB4 is down-regulated in RCC tissues and cell lines, and the low CPEB4 expression is correlated with sho ...[more]

PMID: 34976999

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Project description:BackgroundWilms' tumor 1-associating protein (WTAP) plays an important role in physiological processes and the development of tumor such as cell cycle regulation. The regulation of cell cycle is mainly dependent on cyclins and cyclin-dependent protein kinases (CDKs). Recent studies have shown that CDKs are closely related to the tumor diagnosis, progression and response to treatment. However, their specific biological roles and related mechanism in renal cell carcinoma (RCC) remain unknown.MethodsQuantitative real-time PCR, western blotting and immunohistochemistry were used to detect the expression of WTAP and CDK2. The survival analysis was adopted to explore the association between WTAP expression and the prognosis of RCC. Cells were stably transfected with lentivirus approach and cell proliferation and cell cycle, as well as tumorigenesis in nude mice were performed to assess the effect of WTAP in RCC. RNA immunoprecipitation, Luciferase reporter assay and siRNA were employed to identify the direct binding sites of WTAP with CDK2 transcript. Colony formation assay was conducted to confirm the function of CDK2 in WTAP-induced growth promoting.ResultsIn RCC cell lines and tissues, WTAP was significantly over-expressed. Compared with patients with low expression of WTAP, patients with high expression of WTAP had lower overall survival rate. Additionally, cell function test indicated that cell proliferation abilities in WTAP over-expressed group were enhanced, while WTAP knockdown showed the opposite results. Subcutaneous xenograft tumor model displayed that knockdown of WTAP could impede tumorigenesis in vivo. Mechanism study exhibited that CDK2 expression was positively associated with the expression of WTAP. Moreover, WTAP stabilized CDK2 transcript to enhance CDK2 expression via binding to 3'-UTR of CDK2 transcript. Additionally, specific inhibitors of CDK2 activity and small interfering RNA (siRNA) of CDK2 expression inhibited WTAP-mediated promotion of proliferation.ConclusionsThese findings suggest that WTAP may have an oncogenic role in RCC through physically binding to CDK2 transcript and enhancing its transcript stability which might provide new insights into RCC therapy.

Project description:The progression of clear cell renal cell carcinoma (ccRCC) remains a major challenge in clinical practice, and elucidation of the molecular drivers of malignancy progression is critical for the development of effective therapeutic targets. Recent studies have demonstrated that N6-methyladenosine (m6A) is the most abundant modification of eukaryotic mRNA and plays a key role in tumorigenesis and progression. However, the biological roles and underlying mechanisms of m6A-mediated autophagy in cancers especially in ccRCC remain poorly elucidated. m6A dot blot assay, m6A RNA methylation assay kit and immunofluorescence analysis were used to profile m6A levels in tissue samples and their correlation with autophagic flux. Expression patterns and clinical significance of fat mass and obesity-associated protein (FTO) were determined through bioinformatics analysis, real-time PCR, western blotting, immunohistochemistry. RNA-seq, MeRIP-seq, MeRIP-qRT-PCR, RIP-qRT-PCR, transmission electron microscopy, immunofluorescence analysis and luciferase reporter assay were used to investigate the underlying mechanism of the FTO-autophagy axis. The role of FTO and autophagy in ccRCC progression was evaluated both in vitro and in vivo. Here we found that m6A modification was suppressed and closely related to autophagic flux in ccRCC. Elevated FTO was inhibited by rapamycin, whereas silencing FTO enhanced autophagic flux and impaired ccRCC growth and metastasis. SIK2 was identified as a functional target of m6A-mediated autophagy, thereby prompting FTO to play a conserved and important role in inhibiting autophagy and promoting tumorigenesis through an m6A-IGF2BP2 dependent mechanism. Moreover, the small molecule inhibitor FB23-2 targeting FTO inhibited tumor growth and prolonged survival in the patient-derived xenograft (PDX) model mice, suggesting that FTO is a potential effective therapeutic target for ccRCC. Our findings uncovered the crucial role of FTO/autophagy/SIK2 axis in modulating the progression of ccRCC, suggesting that FTO may serve as a valuable prognostic biomarker and promising therapeutic target in ccRCC.

Dataset Information

CPEB4 Inhibit Cell Proliferation via Upregulating p21 mRNA Stability in Renal Cell Carcinoma.

Publications

CPEB4 Inhibit Cell Proliferation via Upregulating p21 mRNA Stability in Renal Cell Carcinoma.

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