HELLS is an important p53 repression target in liver cancer

The tumor suppressor protein p53 serves as an important barrier against the development and progression of liver cancer. Various p53 responses (e.g. cell cycle arrest, apoptosis, and senescence) are mediated by activation or repression of p53 target genes. To identify previously unrecognized p53 repression targets in liver cancer we used a large scale proteomics approach (LC/MS-MS, > 5000 quantified proteins) in HepG2 cells upon Nutlin-3a treatment (24h). Among the most strikingly decreased proteins we found the chromatin remodeling enzyme "lymphoid specific" helicase HELLS (-2.64 log2 fold-change, q < 0.01). We could validate p53-mediated repression of HELLS by immunoblotting in HepG2 and Huh6 cells upon Nutlin-3a and Camptothecin (CPT) treatment, which was paralleled by a strong decrease in HELLS mRNA as measured by qRT-PCR. Confirming a p53-dependent regulation we could completely rescue decreased HELLS mRNA levels under Nutlin-3a treatment by siRNA mediated knockdown of TP53. Consistent with these findings we observed that HELLS is overexpressed in murine and human hepatocellular carcinoma (HCC) and that HELLS expression correlates with the p53 status.

Our data indicate that HELLS is an important transcriptional repression target of p53 and suggest that mutational or functional inactivation of p53 is an important event leading to HELLS overexpression in liver cancer. The underlying mechanism of p53-mediated repression of HELLS is currently being investigated.