EPIGENETIC MODIFICATIONS REGULATING LIVER HOMEOSTASIS AND TUMORIGENESIS

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide and the fourth cause of death. The major risk factors predisposing to HCC are well known although the lack of reliable markers and efficient pharmacological treatments for HCC patients remains a major problem. In the recent years, several driver mutations have been identified, including signaling molecules and epigenetic modifiers. Specifically, mutations that affect the activity of SWI/SNF chromatin remodeling complex have been commonly reported. Mutational studies clearly indicated a role for epigenetic modifications in HCC development. However, it is still unclear whether SWI/SNF mutations have a role in tumor formation. Our data suggest a new role of Arid1A as one of the key players in HCC tumor development. In our study, we show that ARID1A predispose to HCC formation with the establishment of chronic inflammation. HCC derived from Arid1A deprivation are characterized by the selection of mutations able to induce immune escape. Conversely, the abrogation of all the cBAF complexes, targeting both Arid1A and Arid1B subunits, led to synthetic lethality in a couple of weeks. Moreover, loss of all the Arid1 proteins caused a strong effect on transcriptional profile with loss of all liver specific metabolic pathway. Furthermore, we observed how the absence of both the ARID1 proteins characterized a complete loss of H3K4me1 and H3K27Ac histone modifications on all the FoxA2 targets both on promoter and enhancers. Ultimately, cBAF complex is necessary to maintain the liver metabolism and its homeostasis. Mechanistically, ARID1A loss induced chronic inflammation and, probably indirectly, genomic instability with the upregulation of the interferon pathway due to an increase of micronuclei. This statement imposed a selective pressure which deeply predispose to HCC formation by promoting viral mimicry. All these findings led to actively select mutations to bypass this block induced by the innate immune response activation, among these mutations were found MYC, YAP1, PTEN and S33A β-Catenin mutation.