Serum Response Factor (SRF) Drives the Transcriptional Upregulation of the MDM4 Oncogene in HCC

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2021 Jan 12

PMID 33429878

Citations 4

Authors

Rossella Pellegrino

Abhishek Thavamani

Diego F Calvisi

Jan Budczies

Ariane Neumann

Robert Geffers

Jasmin Kroemer

Damaris Greule

Peter Schirmacher

Alfred Nordheim

Thomas Longerich

Affiliations

Soon will be listed here.

Abstract

Different molecular mechanisms support the overexpression of the mouse double minute homolog 4 (MDM4), a functional p53 inhibitor, in human hepatocellular carcinoma (HCC). However, the transcription factors (TFs) leading to its transcriptional upregulation remain unknown. Following promoter and gene expression analyses, putative TFs were investigated using gene-specific siRNAs, cDNAs, luciferase reporter assays, chromatin immunoprecipitation, and XI-011 drug treatment in vitro. Additionally, MDM4 expression was investigated in transgenic mice. We observed a copy-number-independent upregulation of in human HCCs. Serum response factor (SRF), ELK1 and ELK4 were identified as TFs activating transcription. While SRF was constitutively detected in TF complexes at the promoter, presence of ELK1 and ELK4 was cell-type dependent. Furthermore, MDM4 was upregulated in SRF-VP16-driven murine liver tumors. The pharmacological inhibitor XI-011 exhibited anti- activity by downregulating the TFs driving transcription, which decreased HCC cell viability and increased apoptosis. In conclusion, SRF drives transcriptional upregulation in HCC, acting in concert with either ELK1 or ELK4. The transcriptional regulation of may be a promising target for precision oncology of human HCC, as XI-011 treatment exerts anti- activity independent from the copy number and the status.

Citing Articles

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