Prostate cancer is the second leading cause of cancer death among U.S. men. Clinically, prostate cancer is a heterogeneous disease in which only a small subset of patients will develop aggressive cancer while most cases are indolent and not life threatening. However, the molecular basis for this dichotomy is not fully understood. Furthermore, few biomarkers exist that can predict aggressive versus indolent prostate cancer and guide clinical management of the disease. Recently, our lab discovered SChLAP-1 (Second Chromosome Locus Associated with Prostate), a seven-exon, prostate-specific lncRNA expressed in a subset of localized and metastatic cancers. In vitro and in vivo experiments demonstrated that SChLAP-1 is critical for prostate cancer cell invasiveness and metastasis, a hallmark of aggressive cancers. Additionally, SChLAP-1-correlated gene expression signatures associated with poor patient outcomes and this was confirmed in a large cohort of prostatectomy patients with long-term follow-up;SChLAP-1 expression independently predicts metastasis and prostate cancer-specific mortality. These results indicate that the novel lncRNA SChLAP-1 contributes to the development of lethal prostate cancer;however, the mechanisms regarding SChLAP-1 function remain poorly understood. This study will further investigate the role of SChLAP-1 in prostate cancer biology. Mechanisms underlying SChLAP-1 function will be explored with the following specific aims.
Specific Aim 1 : Identify the chromatin binding sites and protein interactions of SChLAP-1 in prostate cancer cells. ChIRP will be used to identify the SChLAP-1 DNA and protein interactome.
Specific Aim 2 : Determine whether SChLAP-1 regulates PRC2 recruitment and function in prostate cancer cells. Bioinformatics analysis nominated Polycomb Repressive Complex 2 (PRC2) as a concept associated with SChLAP-1. Given the role of PRC2 in prostate cancer and the emerging role of lncRNAs in PRC2 recruitment, it is possible that SChLAP-1 functions in part by mediating PRC2 activity. RIP and ChIP experiments will determine if SChLAP-1 binds to PRC2 and affects its genome-wide localization as well as methylase activity.
Specific Aim 3 : Assess the prognostic utility of SChLAP-1 in predicting distant metastasis (mets) following radical prostatectomy with salvage radiation therapy (SRT) +/- androgen deprivation therapy (ADT) in patients from the RTOG 96-01 trial. In situ hybridization will be used to measure SChLAP-1 expression in prostate cancer tissues from this randomized phase III clinical trial cohort to determine if SChLAP-1 can predict which patients with post-surgical recurrences will benefit from the addition of androgen deprivation therapy to salvage radiation therapy. In summary, we expect the results of this project will improve our understanding of lncRNAs in prostate cancer biology and can potentially be developed for clinical management of the disease.
Prostate cancer is the second leading cause of cancer death among U.S. men, but what causes some cases to progress to aggressive metastatic disease remains poorly understood. Recently, our lab discovered a novel molecular marker of aggressive prostate cancer called, SChLAP-1. In this study, we will investigate the mechanisms underlying SChLAP-1 function and also assess its clinical utility in the management of prostate cancer patients.
|Iyer, Matthew K; Niknafs, Yashar S; Malik, Rohit et al. (2015) The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 47:199-208|
|Sahu, Anirban; Singhal, Udit; Chinnaiyan, Arul M (2015) Long noncoding RNAs in cancer: from function to translation. Trends Cancer 1:93-109|
|Malik, Rohit; Patel, Lalit; Prensner, John R et al. (2014) The lncRNA PCAT29 inhibits oncogenic phenotypes in prostate cancer. Mol Cancer Res 12:1081-7|
|Mehra, Rohit; Shi, Yang; Udager, Aaron M et al. (2014) A novel RNA in situ hybridization assay for the long noncoding RNA SChLAP1 predicts poor clinical outcome after radical prostatectomy in clinically localized prostate cancer. Neoplasia 16:1121-7|
|Raskatov, Jevgenij A; Puckett, James W; Dervan, Peter B (2014) A C-14 labeled Py-Im polyamide localizes to a subcutaneous prostate cancer tumor. Bioorg Med Chem 22:4371-5|
|Prensner, John R; Sahu, Anirban; Iyer, Matthew K et al. (2014) The IncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer. Oncotarget 5:1434-8|
|Prensner, John R; Iyer, Matthew K; Sahu, Anirban et al. (2013) The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet 45:1392-8|