Abstract A1-04: The role of chromatin remodeler CHD1 in genomic alterations and prostate cancer progression

Abstract

Abstract The chromodomain helicase DNA (CHD) binding proteins have been implicated to play a role in genome stability. CHD1 is second only to PTEN as the most frequent homozygously deleted gene in the tumor genome of prostate cancer (PCa). To assess the role of CHD1 in genomic integrity and PCa progression, we performed a comprehensive survey of DNA copy number alterations (CNAs) in the tumor genome among a total of 611 patients from 5 independent cohorts and an association analysis of CHD1 deletion with cancer progression from low (Gleason 6) to high (Gleason ≥ 8) grade tumors. Our data revealed that the frequency of CHD1 deletion significantly increased as cancer progressing from low to intermediate and to high grades, suggesting a role of this CNA in cancer progression. Loss of CHD1 was significantly associated with homozygous deletions at other genomic locations in the tumor genome, and with deletion of MAP3K7. We next evaluated the in vitro and in vivo joint effects of knockdown of CHD1 and the collaborative gene MAP3K7 on tumorigenesis, cell proliferation (Ki67), tumor size, histopathological characteristics, and cancer progression, using shRNA and tissue recombination with rat urogenital mesenchyme and mouse prostate epithelial stem/progenitor cells grafted under the renal capsule and subcutaneous xenografts in nude mice. While suppressing CHD1 expression, in general, resulted in deceased growth of tumor cells vs. shControl cells, concurrently suppressing expression of both CHD1 and MAP3K7 promoted aggressive tumor growth and reduced survival. We finally explored the effect of knockdown of CHD1/MAP3K7 expression in stable cell lines derived human normal prostate epithelial cells and cancer cells on genomic rearrangement via CNA analysis. Although a wide range of CNAs was observed in different cell lines, some of them recapitulated the CNAs that were commonly observed in the tumors of human PCa. Collectively, these data suggest that loss of CHD1 leads to further evolution of cancer cells via genomic instability and combined loss of CHD1 and MAP3K7 drives the progression of PCa. Note: This abstract was not presented at the conference. Citation Format: Wennuan Liu, Lindsey Ulkus Rodrigues, Tao Li, Zheng Zhang, Leah Rider, Lina Romero, Lilly S. Zheng, William B. Isaacs, Scott Cramer, Jianfeng Xu. The role of chromatin remodeler CHD1 in genomic alterations and prostate cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-04.