Abstract PR3: The snoRNP assembly factor SHQ1 is a novel prostate cancer tumor suppressor gene (2012)

Abstract Approximately 50% of prostate tumors harbor the TMPRSS2-ERG translocation, but precisely how this mutation contributes to prostate cancer initiation and progression is unclear. In an effort to identify other causative mutations involved in prostate cancer, we previously performed an integrated genomic analysis of &amp;lt; 200 primary and advanced human prostate cancer samples and cell lines, including assessment of genomic copy-number alterations, mRNA expression, and focused exon sequencing. We identified a recurrent genomic loss, a focal region of chromosome 3p14.1-p13, which was significantly associated with TMPRSS2-ERG translocation. Comparison of copy-number and mRNA expression data implicated at least three genes in this region (FOXP1, RYBP, and SHQ1) as potential cooperative tumor suppressors, which may function in concert with TMPRSS2-ERG translocation. In addition to the genomic loss of SHQ1, we identified point mutations in both SHQ1 and its interacting partner DKC1/dyskerin in primary prostate tumors, leading us to focus on this SHQ1-dyskerin pathway as a potential tumor-suppressive mechanism. SHQ1 is a critical assembly factor for H/ACA-class snoRNA-containing snoRNPs (small nucleolar ribonucleoproteins), of which the core component is the RNA-modifying enzyme DKC1/dyskerin. Downstream targets of dyskerin-containing snoRNPs include the ribosome, splicesome, and telomerase RNPs. DKC1/dyskerin is mutated in the human syndrome dyskeratosis congenita (DC), a disease also caused by mutations in the telomerase complex, which results in bone marrow failure and increased incidence of various neoplasias. We found that, in both human prostate cancer cell lines and mouse fibroblasts in vitro, knockdown of SHQ1 led to increased growth and partial transformation, as evidenced by loss of anchorage-dependence. Additionally, loss of either SHQ1 or dyskerin in vitro led to a global impairment of snoRNA levels, confirming that snoRNA maturation is a major downstream target of the SHQ1-dyskerin pathway in prostate cancer cells. Strikingly, in a mouse model of prostate regeneration by sub-renal capsule implantation, SHQ1-loss in conjunction with ERG expression, but not SHQ1-loss alone, led to development of prostate intraepithelial neoplasia and a low incidence of invasive cancer. Finally, in an in vitro interaction assay, prostate cancer-derived mutations in either SHQ1 or dyskerin impaired their association, to a degree similar to that seen with mutations in dyskerin found in DC. These data, along with the identification of point mutations in both SHQ1 and DKC1/dyskerin in other human cancers, strongly implicate SHQ1 as a novel prostate cancer tumor suppressor gene, potentially acting via disruption of snoRNA maturation. This abstract is also presented as Poster C60. Citation Format: Phillip J. Iaquinta, Chee Wai Chua, Rosario Machado-Pinilla, Haley Hieronymus, John Wongvipat, U. Thomas Meier, Michael Shen, Charles L. Sawyers. The snoRNP assembly factor SHQ1 is a novel prostate cancer tumor suppressor gene [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr PR3.