The role of histone demethylase PHF2 as a tumour suppressor in hepatocellular carcinoma by regulating SRXN1.

Hepatocellular carcinoma is a devastating malignancy with numerous therapeutic targets to guide treatment strategies against the disease. However, given the limited efficacy of current frontline targeted therapies in prolonging the survival for HCC patients both as single agents and in combination, evaluating the potential of epigenome remodelling as a therapeutic target opens unexplored avenues for the clinical management of HCC. In this study, we identified epigenetic vulnerabilities to expand the repertoire of therapeutic strategies for HCC patients. To identify epigenetic regulators essential in HCC, we integrated the functional responses of six HCC cell lines to genetic perturbation of epigenetic regulators using esiRNA with existing data from publicly available databases. Correlation between phenotypic responses of HCC cells to large-scale genetic knockdown of epigenetic regulators and publicly available datasets narrowed down the pool of epigenetic vulnerabilities in HCC to two prospective epigenetic oncogenes (SUPT7L and SMARCC1) and one prospective epigenetic tumour suppressor (PHF2). Subsequently, PHF2 loss-of-function studies in HCC cells were performed through functional, molecular and proteomic analyses. Deeper investigations into PHF2 further established its functional role in mitigating cancer cell growth in vitro. Molecular and proteomic analyses in PHF2-deficient cells further suggested that PHF2 functionally suppresses cancer growth in part through the regulation of the cytoprotective protein, SRXN1. Further characterisation of PHF2-deficient cells were suggestive of independence from the Keap1-Nrf2 pathway. Collectively, our study suggests that PHF2 acts as a candidate epigenetic tumour suppressor in HCC patients through the downregulation of SRXN1, potentially independent of Nrf2.