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Simple Summary  Hepatocellular carcinoma (HCC) represents the most common type of liver cancer and has a poor prognosis. Therefore, there is an urgent need for the identification of new therapeutic options. The mouse double minute homolog 4 ( MDM4 ) gene, a known p53 inhibitor, is upregulated in most HCCs. Here, we aimed to investigate the mechanisms leading to MDM4 transcriptional upregulation and to evaluate whether therapeutic targeting of these mechanisms might represent a suitable approach for future therapy. Using human HCC cell lines, a mouse model, and human HCC cohorts, we have identified serum response factor (SRF), ETS transcription factors ELK1 and ELK4 as transcription factors (TFs) driving  MDM4  expression. Treatment of HCC cell lines with XI-011, a pharmaceutical inhibitor of  MDM4  transcription, reduced the expression of both the TFs and MDM4 and impaired tumor growth, suggesting that targeting the  MDM4  transcription may provide a rationale for future targeted therapy of HCC.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  SRF-VP16 iHep   transgenic mice. We observed a copy-number-independent upregulation of  MDM4  in human HCCs. Serum response factor (SRF), ELK1 and ELK4 were identified as TFs activating  MDM4  transcription. While SRF was constitutively detected in TF complexes at the  MDM4  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- MDM4  activity by downregulating the TFs driving  MDM4  transcription, which decreased HCC cell viability and increased apoptosis. In conclusion, SRF drives transcriptional  MDM4  upregulation in HCC, acting in concert with either ELK1 or ELK4. The transcriptional regulation of  MDM4  may be a promising target for precision oncology of human HCC, as XI-011 treatment exerts anti- MDM4  activity independent from the  MDM4  copy number and the  p53  status.

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