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 important senescence markers in both tumor and normal cells. Evidence point to Wig-1 playing an inhibitory role on the mRNAs of histone modifying enzymes, thereby acting on well established senescence markers of gene expression and chromatin regulation.

Citation Format: Fredrik Jerhammar, Cinzia Bersani, Dijana Djureinovic, Patrick Micke, Klas G. Wiman. The role of the p53 target Wig-1 in senescence and cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 110. doi:10.1158/1538-7445.AM2015-110

©2015 American Association for Cancer Research.
2015