The Role of Long Noncoding RNA SChLAP1 in Prostate Cancer

Abstract

Prostate cancer is the most common malignancy in U.S. men, accounting for nearly 30,000 deaths annually. While the majority of prostate cancers are indolent, a subset of patients has aggressive disease. However, the molecular basis for this clinical heterogeneity remains incompletely understood.

Long noncoding RNAs (lncRNAs) are an emerging class of regulatory molecules implicated in a diverse range of human malignancies. Here, SChLAP1 is identified as a novel, highly prognostic lncRNA that is expressed in 15-30% of prostate cancers. Functionally, SChLAP1 coordinates cancer cell invasion in vitro and metastatic spread in vivo. Mechanistically, SChLAP1 interacts with and antagonizes the tumor-suppressive SWI/SNF nucleosome-remodeling complex.

While deleterious SWI/SNF mutations occur in 20% of all cancers, they are relatively rare in prostate cancer. Within prostate cancer, SWI/SNF mutations are associated with low SChLAP1 expression, suggesting that high SChLAP1 expression may represent a mutation-independent modality of SWI/SNF inhibition. Employing a previously described antagonistic model between SWI/SNF and Polycomb Repressive Complex 2 (PRC2), SChLAP1 is found to enhance PRC2 function in prostate cancer. Additionally, SChLAP1-expressing cells are more sensitive to pharmacologic EZH2 inhibition.

Further characterization of SChLAP1 reveals a 250bp region near the 3’-end that mediates its invasive phenotype and coordinates its interaction with SWI/SNF. Additionally, SChLAP1 interacts with BRG1-containing but not BRM-containing SWI/SNF complexes, and knockdown of BRM in SChLAP1-expressing cells exposes a synthetic lethal vulnerability in prostate cancer.

Finally, the largest biomarker discovery project to date in prostate cancer identifies SChLAP1 as one of the best genes for predicting metastatic progression. Characterization of SChLAP1 expression by in situ hybridization shows that SChLAP1 expression is enriched in metastatic samples. Additionally, SChLAP1 can be detected in patient urine samples and may be useful as a non-invasive biomarker. Lastly, targeting SChLAP1 with antisense oligonucleotides (ASO) suggests that directly targeting SChLAP1 may be an effective therapeutic strategy in prostate cancer.

Taken together, this work defines an essential role for SChLAP1 in aggressive prostate cancer, uncovers novel aspects of lncRNA biology, and has broad implications for cancer biology.