Abstract SY12-04: Regulation of normal and cancer stem cell self renewal and senescence by USP16

Abstract

Abstract Down syndrome (DS) is a complex clinical syndrome associated with multiple pathological conditions including deficits in motor skills and learning. DS has also been associated with early onset and higher incidence of aging-related phenomena such as Alzheimer's disease. Recently, it has been proposed that the aging process is correlated with an impaired or exhausted ability of stem cells to self-renew. we show that in Ts65Dn mice, trisomic for 132 genes homologous to HSA21, triplication of Usp16 reduces self-renewal of hematopoietic stem cells and expansion of mammary epithelial cells, neural progenitors, and fibroblasts. Moreover, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from H2AK119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal USP16 allele or by shRNAs, largely rescues all these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and post-natal neural progenitors while downregulation of USP16 partially rescues the proliferation defects of DS fibroblasts. Taken together, these results suggest that USP16 plays an important role in antagonizing the self-renewal and/or senescence pathways in Down syndrome and could serve as an attractive target to ameliorate some of the associated pathologies. Down syndrome patients also have a decreased incidence of solid tumors including breast cancer. The potential role of USP16 in human breast cancer will be discussed. Citation Format: Michael F. Clarke. Regulation of normal and cancer stem cell self renewal and senescence by USP16. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY12-04. doi:10.1158/1538-7445.AM2014-SY12-04