Transcription factor FOXM1 promotes hepatocellular carcinoma malignant progression through activation of the WNT pathway by binding to SETDB1

Abstract

Background: FOXM1 is a transcription factor confirmed by studies to promote the development of hepatocellular carcinoma (HCC) and various other cancers, yet the molecular mechanism remains rather enigmatic. This study attempted to unveil the function and regulatory mechanism of FOXM1 in the progression of HCC.

Methods: Bioinformatics methods first analyzed the expression of FOXM1 in HCC tissues and then screened target genes downstream of FOXM1. Possible pathways of the target gene were specified through Gene Set Enrichment Analysis (GSEA). After using qRT-PCR to measure the expression of FOXM1 and its downstream regulatory gene SETDB1 in HCC tissues, ChIP and dual-luciferase assays were employed and verified the binding relationship between FOXM1 and the promoter of SETDB1. Then the effects of the FOXM1/SETDB1/Wnt pathway on the proliferation, migration, and invasion of HCC cells were profiled by CCK-8, colony formation, wound healing, and transwell assays. WNT and EMT-related protein expression levels were detected by western blot and immunofluorescence assay, respectively.

Results: The bioinformatics prediction showed that SETDB1 was the target downstream of FOXM1, and their binding relationship was verified by ChIP and dual-luciferase assays. Cell experiments showed that FOXM1 could enhance the proliferative, migratory, and invasive abilities of HCC cells through binding to SETDB1. Rescue assay suggested that the activation of key genes of the WNT pathway and EMT-related genes were part of the regulatory mechanism that FOXM1 bound to SETDB1.

Conclusion: This study found that FOXM1 could bind with SETDB1 and hence activate the WNT signaling pathway to promote the malignant progression of HCC. It indicated that FOXM1 could be the possible target for treating HCC.

Keywords: FOXM1; Hepatocellular carcinoma; SETDB1; WNT pathway.