Dataset Information

FBX8 degrades GSTP1 through ubiquitination to suppress colorectal cancer progression.

ABSTRACT: F-box only protein 8 (FBX8), as a critical component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases, has been associated with several malignancies through interacting with a member of proteins. However, the substrates of FBX8 for destruction in the progression of colorectal carcinoma (CRC) need to be explored. Here, we show that loss of FBX8 accelerates chemical-induced colon tumorigenesis. FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC. GSTP1 promotes the proliferation, invasion, and metastasis of CRC cells. Furthermore, GSTP1 is upregulated in CRC tissue samples and predicts poor prognosis of CRC patients. The inactivation of FBX8 negatively correlated with increased levels and stability of GSTP1 in clinical CRC tissues and FBX8 knockout transgenic mice. These findings identify a novel ubiquitination pathway as FBX8-GSTP1 axis that regulates the progression of CRC, which might be a potential prognostic biomarker for CRC patients.

SUBMITTER: FeiFei W

PROVIDER: S-EPMC6484082 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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FBX8 degrades GSTP1 through ubiquitination to suppress colorectal cancer progression.

FeiFei Wang W HongHai Xu X YongRong Yan Y PingXiang Wu W JianHua Wu W XiaoHui Zhu Z JiaoYing Li L JingBo Sun S Kun Zhou Z XiaoLi Ren R Lu Qi Q XiaoLiang Lan L ZhiQiang Cheng C Na Tang T WenTing Liao L YanQing Ding D Li Liang L

Cell death & disease 20190425 5

F-box only protein 8 (FBX8), as a critical component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases, has been associated with several malignancies through interacting with a member of proteins. However, the substrates of FBX8 for destruction in the progression of colorectal carcinoma (CRC) need to be explored. Here, we show that loss of FBX8 accelerates chemical-induced colon tumorigenesis. FBX8 directly targets GSTP1 for ubiquitin-mediated proteasome degradation in CRC. GSTP1 promotes the pr ...[more]

PMID: 31024008

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Project description:BackgroundColorectal cancer (CRC) is characterized by its aggressiveness and high fatality rate. Long noncoding RNAs (lncRNAs) as molecular scaffolding in CRC have received little attention.MethodsThe TCGA database was used to find putative anti-oncogenic lncRNAs in CRC. The effect of FENDRR on CRC was evaluated using the colony formation assay, transwell assays, and wound healing assays, and FENDRR expression was validated by qRT-PCR. The location of the FENDRR binding proteins was determined by an RNA pull-down experiment, and the retrieved proteins were recognized by mass spectrometry. RNA immunoprecipitation (RIP) studies were used to demonstrate the interaction of GSTP1, FBX8, and FENDRR. Co-IP and immunofluorescence were utilized to confirm the connection between GSTP1 and FBX8. To determine the precise signaling pathways implicated in the action of FENDRR in CRC, we performed next-generation sequencing (NGS) on CRC cells transfected with a vector overexpressing FENDRR.ResultsThe expression of FENDRR was significantly downregulated in CRC tissue and cells. The results of the function experiments showed that overexpression of FENDRR reduced CRC cells' ability to proliferation, invasion, migration and tube formation. In terms of mechanism, FENDRR could bind both GSTP1 and FBX8, act as a molecular scaffold, and utilize FBX8 to regulate the stability of GSTP1's protein. Additionally, the outcomes of NGS and qRT-PCR demonstrated that the expression of genes linked to the HIF-1 pathway was down-regulated following FENDRR overexpression. Lastly, rescue tests demonstrated that overexpression of GSTP1 in CRC cells could completely restore the inhibition induced by FENDRR.ConclusionIn this study, we found that the molecular scaffolding protein FENDRR regulates the ubiquitination of GSTP1 and the suppression of the HIF-1 signaling pathway in the development of CRC. Our research provides more evidence of FENDRR's crucial role in the emergence of CRC and identifies it as a potential therapeutic target for CRC patients.

Dataset Information

FBX8 degrades GSTP1 through ubiquitination to suppress colorectal cancer progression.

Publications

FBX8 degrades GSTP1 through ubiquitination to suppress colorectal cancer progression.

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