Abstract SY20-01: CHD5: Chromosome engineering, chromatin dynamics and cancer

Abstract

Abstract Although 1p36 loss has been documented for decades and a variety of malignancies have this particular lesion, the tumor suppressor mapping to this genomic interval had not been identified. Using chromosome engineering to create models with gain and loss of the region of the mouse genome corresponding to human 1p36, we pinpointed a potent tumor suppressive interval, identified Chromodomain Helicase DNA-binding domain protein 5 (CHD5) as the causative gene in the region, elucidated molecular pathways induced by CHD5, and demonstrated that CHD5 is frequently deleted in human cancer. The discovery of CHD5 as a tumor suppressor has had a major impact in the cancer field. Indeed, it is now appreciated that CHD5 is mutated in cancers of the breast, ovary, colon, and prostate, as well as in melanoma, glioma, and neuroblastoma. Furthermore, CHD5 status is a prognostic indicator of patient survival following anti-cancer therapy. Still, the mechanism by which CHD5 exerts its tumor suppressive role is barely understood. CHD5 belongs to the CHD family of SWI-SNF-like ATP dependent-chromatin remodeling proteins; however, the role of CHD5 in modulating chromatin dynamics has not been reported. Here, we show that CHD5's tumor suppressive function is dependent on its tandem plant homeodomains (PHDs)—modules that in several other chromatin-remodeling proteins regulate transcription by binding to specific covalent modifications on histone tails. Each of the two PHDs of CHD5 preferentially bind unmethylated H3K4 (H3K4me0), an interaction abrogated by methylation of H3K4 but unaffected by modification of H3K9. Consistent with its binding specificity in vitro, genome-wide ChIP-sequencing indicates that CHD5 binds loci lacking highly methylated H3K4 marks in vivo. Both loss- and gain-of-function studies reveal that CHD5 modulates transcription, and furthermore, that CHD5 is a potent inhibitor of cellular proliferation. Mutation of residues within the PHDs of CHD5 that abolish H3K4me0 binding effectively abrogate the ability of CHD5 to modulate expression of target genes as well as to inhibit proliferation, leading to tumorigenesis in vivo. These findings identify CHD5 as a member of a newly appreciated class of H3K4me0-binding PHD containing proteins and reveal a critical role for this interaction in facilitating CHD5's cellular function, providing new insight into the molecular mechanism responsible for the tumor suppressive role of CHD5. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY20-01. doi:1538-7445.AM2012-SY20-01