Abstract IA-1: From chromosome engineering to chromatin remodeler: CHD5 is a tumor suppressor mapping to human 1p36

Abstract

Abstract Deletions encompassing the 1p36 region of human chromosome 1 have been associated with a spectrum of malignancies, however the tumor suppressor had not been identified. In an effort to identify tumor suppressors within this interval, we used chromosome engineering to generate mouse models with loss- and gain of regions of the genome corresponding to human 1p36. This strategy allowed us to identify a 4.3 megabase interval with potent tumor suppressive activity. Whereas loss of this region caused a marked increase in cellular proliferation that culminated in cancer in vivo, gain of the same interval triggered excessive tumor suppression as observed by augmented cellular senescence in cultured cells and apoptosis in vivo. Using genetic and molecular analyses, we identified the chromatin remodeling protein Chromodomain, helicase, DNA-binding domain protein 5 (Chd5) as the tumor suppressor within the interval, and revealed that Chd5 functions as a master regulator that facilitates p16/Rb- and p19/p53-modulated pathways. Analyses of human gliomas revealed that CHD5 is frequently deleted, suggesting that CHD5 loss contributes to malignancy. Here I will present our current efforts aimed at elucidating the epigenetic role of CHD5 in tumor suppression. Citation Information: Cancer Res 2009;69(23 Suppl):IA-1.