Dysregulation of the epigenetic regulator SETDB1 in liver carcinogenesis-more than one way to skin a cat.

Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers worldwide. Its development is considered a step-wise process in which genetic and epigenetic alterations lead to the activation of oncogenes and the inactivation of tumor suppressor genes. In contrast to genetic alterations, epigenetic changes that include aberrant methylation, histone modification and RNA interference do not alter the genetic code, but affect the level of mRNA transcripts. In addition, these epigenetic alterations may influence each other. In their elegant study, Wong et al. analyzed the expression of 591 known epigenetic regulators in human HBV-induced HCC by transcriptome sequencing. They identified SETDB1 as the most significantly up-regulated epigenetic regulator in human HCC. In their cohort SETDB1 overexpression was associated with metastasis formation and poorer prognosis of HCC patients. Interestingly, the authors observed several complementary mechanisms contributing to the upregulation of SETDB1 in HCC cells. Besides copy number gains at the SETDB1 gene locus at chromosome 1q21 enhanced SETDB1 transcription mediated by the transcription factor SP1 could be detected. Finally, Wong and colleagues showed that SETDB1 is a target of miR-29, which is frequently downregulated in human HCCs. Taken together, SETDB1 overexpression is mediated by several complementary acting mechanisms suggesting that upregulation of SETDB1 may be a hallmark of HCC progression. This study warrants for independent validation, analyses of a larger series of non-HBV-associated human HCCs, and for further testing of methyltransferase inhibitors as well as molecules targeting SETDB1 in (pre-)clinical studies.