Abstract 110: The role of the p53 target Wig-1 in senescence and cancer

The wild type p53-induced gene 1, Wig-1 (also known as Zmat3 or PAG608) binds to AU-rich elements in mRNAs and thereby regulates important tumor associated factors including p53, FAS, and N-Myc.Focusing on normal human diploid fibroblasts (HDF), we are now exploring the role of Wig-1 in senescence. SiRNA-mediated Wig-1 depletion increases senescence markers such as Beta-galactosidase staining, H3K9me3, H4K20me3, and p21. Also, Wig-1 is spontaneously downregulated in cells undergoing replicative senescence.The trimethylation of lysine 9 on histone 3 (H3K9me3) is an established marker of cellular senescence and increases upon siRNA-mediated Wig-1 knockdown in HDF cells. It is also increased in late passage (senescent) fibroblasts that express low Wig-1 levels.Our RNA-immunoprecipitation sequencing (RIP-seq) data of tumor cells shows that Wig-1 binds histone-modifying enzymes SUV39H2 (which trimethylates H3K9), and subunits of PP1 (protein phosphatase 1, which dephosphorylates H3T10). These mRNAs have AU-rich elements in the 3´UTR. Importantly, we have observed that both SUV39H2 and its corresponding methylation (H3K9me3) is increased upon Wig-1 silencing.In a cohort of 350 lung cancer patients, we found Wig-1 gene amplification in a large portion of squamous cell carcinomas, whereas in lung adenocarcinomas the Wig-1 gene was unchanged. Interestingly, strong Wig-1 staining in this cohort correlates to worse prognosis.We think Wig-1 attenuates senescence via downregulating impor...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Biology Source Type: research