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The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex.

ABSTRACT: Prostate cancers remain indolent in the majority of individuals but behave aggressively in a minority. The molecular basis for this clinical heterogeneity remains incompletely understood. Here we characterize a long noncoding RNA termed SChLAP1 (second chromosome locus associated with prostate-1; also called LINC00913) that is overexpressed in a subset of prostate cancers. SChLAP1 levels independently predict poor outcomes, including metastasis and prostate cancer-specific mortality. In vitro and in vivo gain-of-function and loss-of-function experiments indicate that SChLAP1 is critical for cancer cell invasiveness and metastasis. Mechanistically, SChLAP1 antagonizes the genome-wide localization and regulatory functions of the SWI/SNF chromatin-modifying complex. These results suggest that SChLAP1 contributes to the development of lethal cancer at least in part by antagonizing the tumor-suppressive functions of the SWI/SNF complex.

SUBMITTER: Prensner JR

PROVIDER: S-EPMC3812362 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex.

Prensner John R JR Iyer Matthew K MK Sahu Anirban A Asangani Irfan A IA Cao Qi Q Patel Lalit L Vergara Ismael A IA Davicioni Elai E Erho Nicholas N Ghadessi Mercedeh M Jenkins Robert B RB Triche Timothy J TJ Malik Rohit R Bedenis Rachel R McGregor Natalie N Ma Teng T Chen Wei W Han Sumin S Jing Xiaojun X Cao Xuhong X Wang Xiaoju X Chandler Benjamin B Yan Wei W Siddiqui Javed J Kunju Lakshmi P LP Dhanasekaran Saravana M SM Pienta Kenneth J KJ Feng Felix Y FY Chinnaiyan Arul M AM

Nature genetics 20130929 11

Prostate cancers remain indolent in the majority of individuals but behave aggressively in a minority. The molecular basis for this clinical heterogeneity remains incompletely understood. Here we characterize a long noncoding RNA termed SChLAP1 (second chromosome locus associated with prostate-1; also called LINC00913) that is overexpressed in a subset of prostate cancers. SChLAP1 levels independently predict poor outcomes, including metastasis and prostate cancer-specific mortality. In vitro an ...[more]

PMID: 24076601

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Project description:Dedifferentiated/undifferentiated endometrial carcinoma (DDEC/UEC) is an endometrial cancer characterized by the presence of histologically undifferentiated carcinoma. Genomic inactivation of core switch/sucrose nonfermentable (SWI/SNF) complex proteins was recently identified in approximately two-thirds of DDEC/UEC. The aim of this study was to delineate the clinical behavior of SWI/SNF-deficient DDEC/UEC in comparison to SWI/SNF-intact DDEC/UEC. The study cohort consisted of 56 SWI/SNF-deficient DDEC/UEC (2 POLE-mutated), which showed either SMARCA4 (BRG1) loss, ARID1A/1B co-loss, or SMARCB1 (INI1) loss in the undifferentiated tumor, and 26 SWI/SNF-intact DDEC/UEC (4 POLE-mutated). The average age at diagnosis was 61 years for patients with SWI/SNF-deficient tumors and 64 years for SWI/SNF-intact tumors. Mismatch repair (MMR) protein deficiency was seen in 66% of SWI/SNF-deficient and 50% of SWI/SNF-intact tumors. At initial presentation, 55% of patients with SWI/SNF-deficient tumors had extrauterine disease spread in contrast to 38% of patients with SWI/SNF-intact tumors. The 2-year disease specific survival (DSS) for stages I and II disease was 65% for SWI/SNF deficient tumors relative to 100% for SWI/SNF-intact tumors (p = 0.042). For patients with stages III and IV disease, the median survival was 4 months for SWI/SNF-deficient tumors compared to 36 months for SWI/SNF-intact tumors (p = 0.0003). All six patients with POLE-mutated tumors, including one with stage IV SWI/SNF-deficient tumor were alive with no evidence of disease. Among the patients with advanced stage SWI/SNF-deficient tumors, 68% (21 of 31) received adjuvant or neoadjuvant chemotherapy (platinum/taxane-based) and all except the patient with a POLE-mutated tumor (20 of 21) experienced disease progression either during chemotherapy or within 4 months after its completion. These findings show that core SWI/SNF-deficiency defines a highly aggressive group of undifferentiated cancer characterized by rapid disease progression that is refractory to conventional platinum/taxane-based chemotherapy. This underscores the importance of accurate clinical recognition of this aggressive tumor and the need to consider alternative systemic therapy for these tumors.

Dataset Information

The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex.

Publications

The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex.

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