HELLS Is Negatively Regulated by Wild-Type P53 in Liver Cancer by a Mechanism Involving P21 and FOXM1

Abstract

The major tumor suppressor P53 (<i>TP53</i>) acts primarily as a transcription factor by activating or repressing subsets of its numerous target genes, resulting in different cellular outcomes (e.g., cell cycle arrest, apoptosis and senescence). P53-dependent gene regulation is linked to several aspects of chromatin remodeling; however, regulation of chromatin-modifying enzymes by P53 is poorly understood in hepatocarcinogenesis. Herein, we identified Helicase, lymphoid specific (<i>HELLS</i>), a major epigenetic regulator in liver cancer, as a strong and selective P53 repression target within the SNF2-like helicase family. The underlying regulatory mechanism involved P53-dependent induction of P21 (<i>CDKN1A</i>), leading to repression of Forkhead Box Protein M1 (<i>FOXM1</i>) that in turn resulted in downregulation of <i>HELLS</i> expression. Supporting our in vitro data, we found higher expression of HELLS in murine HCCs arising in a <i>Trp53-/-</i> background compared to <i>Trp53+/+</i> HCCs as well as a strong and highly significant correlation between <i>HELLS</i> and <i>FOXM1</i> expression in different HCC patient cohorts. Our data suggest that functional or mutational inactivation of P53 substantially contributes to overexpression of HELLS in HCC patients and indicates a previously unstudied aspect of P53's ability to suppress liver cancer formation.