Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>CHD1 is a member of the super-family of chromatin modifier proteins, and is characterized by the presence of several chromo-domains as well as an ATP dependent helicase domain. A multitude of studies across several model systems have demonstrated that CHD1 functions as a transcriptional co-activator, responsible for efficient RNA polymerase II (RNA pol II) ejection from the transcriptional start site as well as maintenance of RNA pol II processivity across the gene body. This is accomplished largely though nucleosome remodeling ahead of RNA pol II, which efficiently reorganizes nucleosome position to allow for optimal RNA pol II function. Consequently, as CHD1 plays a critical role in transcriptional competency, tumor associated deletions and/or mutations of the CHD1 gene that compromise its function are rare. Interestingly, prostate cancer proves to be the exception, where the CHD1 locus is deleted with high frequency in primary disease. Tumors harboring homozygous deletion of CHD1 belong to a subclass of prostate cancer that are enriched for either SPOP or FOXA1 mutations, suggesting a prostate-specific, tumor suppressive role for CHD1 in this genomic context. Importantly, while the oncogenic functions of both FOXA1 and SPOP mutations have been largely defined, little is known as to how CHD1 loss contributes to tumor initiation or progression. Here, using 3D organoid cultures derived from GEM models of inducible CHD1 loss, prostate specific cells were found to have dramatically altered transcriptionally competency upon CHD1 depletion. These events were correlated with an aberrant, tumor-associated transcriptome, resulting in changes in morphology and growth. Furthermore, while genome wide assessment of CHD1 occupancy in human prostate cancer models uncovered an enrichment of CHD1 at sites of active transcription, loss of CHD1 did not dramatically affect expression of genes associated with tumor progression. Inversely, genomic loss of CHD1 was associated with changes in lineage dependent markers, suggesting that a major function of CHD1 is to regulate the differentiation state of prostate cells. Collectively, these data help to define the tumor suppressive role for CHD1 in prostate cancer tumorigenesis, and suggest that loss of CHD1 could alter the function of key transcriptional regulators associated with prostate cancer initiation and progression.</jats:p>
<jats:p>Citation Format: Michael A. Augello, Mirjam Blattner-Johnson, Mark Rubin, Christopher Barbieri. Consequence of the tumor-associated deletion of CHD1 on transcriptional output and tumor progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1974.</jats:p>