Abstract 2959: The tumor suppressor CHD5 is an epigenetic regulator of neuronal cell fate

Abstract

Abstract Genomic lesions affecting the 1p36 chromosomal region are prevalent in variety of human malignancies, yet the tumor suppressor in this region had not been identified. We used chromosome engineering to create a series of mouse models with lesions spanning the 1p36-analagous region. These gain and loss-of-function models allowed us to pinpoint a potent tumor suppressive interval that when deleted predisposes to cancer and when duplicated causes excessive tumor suppression. We identified Chromodomain Helicase DNA-binding domain protein 5 (CHD5) as the causative gene in the region, defined CHD5 as an inducer of the tumor suppressive network encoded at the Cdkn2 locus, and demonstrated that CHD5 is frequently deleted in human glioma. 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, and furthermore, that robust CHD5 expression is a favorable indicator of patient survival following anti-cancer therapy. Although ample evidence from human studies indicates that CHD5 plays a pivotal role in cancer, the mechanism responsible for tumor suppression is not well understood. CHD5 belongs to the CHD family of ATP-dependent chromatin remodeling proteins, yet CHD5's role in modulating chromatin and the consequence of CHD5 deficiency in vivo was unknown. We discovered that CHD5's tumor suppressive function is dependent on its dual plant homeodomains (PHDs)_motifs that bind specifically marked histones. The PHDs of CHD5 preferentially bind unmodified histone 3 (H3), an interaction essential for CHD5's ability to inhibit proliferation, to modulate transcription, and to suppress tumorigenesis in vivo. We recently defined CHD5 as a regulator of chromatin-mediated dynamics essential for neuronal differentiation. Whereas neural stem cells (NSCs) normally have the capacity to differentiate into neurons, NSCs from Chd5-deficient mice retain stem-like characteristics and differentiate into astrocytes at the expense of neurons. We discovered that H3K27me3_a repressive chromatin mark implicated in cancer_is depleted by CHD5 deficiency. We show that CHD5 rescues the de-differentiated phenotype of CHD5 deficient NSCs, while re-establishing global levels of H3K27me3. Our findings define CHD5 as a dosage-sensitive tumor suppressor, identify CHD5 as a member of a newly appreciated class of H3-binding PHD-containing proteins, and reveal a critical role for CHD5 in dictating stem cell fate. This provides new insight into the epigenetic mechanisms responsible for CHD5's tumor suppressive role that when perturbed, set the stage for cancer. Citation Format: Alea A. Mills, Dong-Woo Hwang. The tumor suppressor CHD5 is an epigenetic regulator of neuronal cell fate. [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 2959. doi:10.1158/1538-7445.AM2014-2959