KDM5C Represses FASN-Mediated Lipid Metabolism to Exert Tumor Suppressor Activity in Intrahepatic Cholangiocarcinoma.

Bo Zhang,Hui Li,Min Xiao,Lei Guo,Meng-Xi Wang,Qing-Hai Ye,Shan-He Yu,Bing-Hai Zhou

doi:10.3389/fonc.2020.01025

Abstract

Background: KDM5C is a histone H3K4-specific demethylase, which has multiple biological functions during development and disease. However, the role of KDM5C in intrahepatic cholangiocarcinoma (ICC) remains unknown.Methods: Expression levels of KDM5C in ICC patients were determined by qRT-PCR, western blotting and immunohistochemical assay. The functions of KDM5C in cell proliferation and invasion were determined in human ICC cells and mouse xenograft model using KDM5C overexpression and knockdown strategies in vivo. RNA-seq analysis was applied to investigate the transcriptional program of KDM5C. In addition, ChIP-qPCR was used to determine the regulation of FASN by KDM5C.Results: Here, we show that KDM5C was downregulated in human ICC, where its diminished expression was associated with poor prognosis. ICC cell proliferation and invasion were inhibited by KDM5C overexpression. Moreover, KDM5C suppressed ICC proliferation and metastasis in vivo. RNA-sequencing showed that KDM5C inhibits key signal pathways of cell proliferation, cell invasion and fatty acid metabolism. ChIP-qPCR revealed that overexpression of KDM5C led to the reduction of H3K4me3 on the promoter and the corresponding downregulation of the expression of FASN, which represents the major target gene of KDM5C to mediate the proliferation and invasion of ICC cells.Conclusions: Our results revealed the role of KDM5C as a novel tumor suppressor in ICC largely by repressing FASN-mediated lipid acid metabolism and thus KDM5C may contribute to the pathogenesis of ICC.

Highlights

Intrahepatic cholangiocarcinoma (ICC) accounts for 10–20% of newly diagnosed liver cancers, which is the second most common primary malignancy in the liver only after hepatocellular carcinoma (HCC) [1, 2]
We demonstrate that ICC patients have dramatically lower expression of Lysine-specific demethylase 5C (KDM5C), which was consistent with the finding that KDM5C overexpression inhibits proliferation and invasion of ICC cells, which is largely ascribed to its modulation of Fatty acid synthase (FASN) expression
Patients with high KDM5C expression had both higher overall survival (p = 0.002) and better disease-free survival (p = 0.030) (Figures 1E,F and Table S1) than the low KDM5C expression group. These results suggest that, contrary to the increased expression of KDM5C in hepatic carcinoma, the decreased expression of KDM5C in ICC is correlated with a poor prognosis

Summary

Introduction

Intrahepatic cholangiocarcinoma (ICC) accounts for 10–20% of newly diagnosed liver cancers, which is the second most common primary malignancy in the liver only after hepatocellular carcinoma (HCC) [1, 2]. KDM5C Inhibits ICC via FASN-Repression to epigenetic remodeling, transcriptional regulation and cell metabolism of ICC cells [4]. Dysregulation of epigenetic modifications especially DNA methylation and histone modifications induces aberrant gene expression, making individuals prone to diet-related disorders, such as cancer [5]. Abnormal histone modifications can be associated with metabolism-related tumors, reinforcing the concept that histone modifiers have a critical role in these processes [6,7,8,9]. KDM5C is a histone H3K4-specific demethylase, which has multiple biological functions during development and disease. The role of KDM5C in intrahepatic cholangiocarcinoma (ICC) remains unknown

Methods

Results

Discussion

Conclusion