KDM5c Promotes Colon Cancer Cell Proliferation Through the FBXW7-c-Jun Regulatory Axis.

Haishan Lin,Lei Zhao,Bangwei Cao,Nina Ma,Guowei Yang

doi:10.3389/fonc.2020.535449

Abstract

KDM5c is a histone demethylase that specifically demethylates trimethylated and dimethylated H3 Lys-4 to play a central role in transcriptional repression. C-Jun is a proto-oncogene and promotes cell proliferation when ectopically accumulated, but can be ubiquitinated by SCF (FBXW7), leading to its degradation. FBXW7 is an E3 ubiquitin ligase of c-Jun, and exhibits carcinostasis in colon cancer. Here, we report that overexpression of KDM5c in human colon cancer cells results in attenuated FBXW7 transcription and accumulated c-Jun protein, leading to increased proliferation of colon cancer cells. We show that overexpression of KDM5c can result in increased c-Jun protein levels and decreased ubiquitin levels, with no significant change in mRNA levels of c-Jun. KDM5c overexpression blocks the ubiquitin-proteasome proteolytic pathway of c-Jun by down-regulating the expression of FBXW7. KDM5c down-regulation of FBXW7 occurs by demethylation of H3K4me3 at TSS and downstream of the FBXW7 gene. And interaction of KDM5c with H3K4me3 downstream of FBXW7 gene may be followed by recruitment of DNMT3b to methylate the spatially close CpG island located near the FBXW7 TSS. This methylation represses FBXW7 gene expression, which can reduce c-Jun degradation via the ubiquitin-proteasome pathway. TCGA database analysis revealed high expression of KDM5c in colon cancer tissues. KDM5c expression in colon cancer was correlated with poor overall survival of patients in the first 7 years. Data from TCGA showed that high expression of KDM5c was correlated with high DNA methylation of the FBXW7 gene, but was not positively correlated with methylation of the Jun gene. These results suggest that KDM5c regulation of colon cell proliferation is mainly mediated by the KDM5c-FBXW7-c-Jun axis.

Highlights

Colorectal cancer (CRC) is the third most prevalent malignancy and ranks second in mortality among solid tumors, representing a serious public health problem worldwide [1]
Previous work has correlated KDM5c to various cancers, but whether KDM5c plays a role in colon cancer progression remains unknown
We increased the amount of KDM5c by transfected KDM5c plasmid and used western blot to confirm increased KDM5c protein level in both RKO and HCT-8 cells compared to the wild-type cells, but decreased H3K4me3 protein level, consistent with the demethylase function of KDM5c

Summary

Introduction

Colorectal cancer (CRC) is the third most prevalent malignancy and ranks second in mortality among solid tumors, representing a serious public health problem worldwide [1]. Driver gene mutations account for a large proportion of colon malignant tumors cases, but mutated driver genes have not been identified for some colon cancer cases, suggesting that epigenetic changes act as an important supplement to genetic changes to cause tumors. We applied an epigenetic perspective to investigate new potential therapeutic targets for colorectal cancer. Recent evidence has indicated that epigenetic mutations are strongly involved in cancer initiation and progression [5]. These mutations have been detected widely across the genome, KDM5c-FBXW7-c-Jun Promoted Colon Cancer Cell Proliferation and are considered a more important contributor to tumor heterogeneity. Epigenetic mutations are promising targets for epidemiological and physiopathological studies, and therapeutic response evaluation and drug design [8]

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