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

Prensner, John R.; Iyer, Matthew K.; Sahu, Anirban; Asangani, Irfan A.; Cao, Qi; Patel, Lalit; Vergara, Ismael A.; Davicioni, Elai; Erho, Nicholas; Ghadessi, Mercedeh; Jenkins, Robert B.; Triche, Timothy J.; Malik, Rohit; Bedenis, Rachel; McGregor, Natalie; Ma, Teng; Chen, Wei; Han, Sumin; Jing, Xiaojun; Cao, Xuhong; Wang, Xiaoju; Chandler, Benjamin C.; Yan, Wei; Siddiqui, Javed; Kunju, Lakshmi P.; Dhanasekaran, Saravana M.; Pienta, Kenneth J.; Feng, Felix Y.; Chinnaiyan, Arul M.

doi:10.1038/ng.2771

Cited by 622 publications

(582 citation statements)

References 59 publications

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“…http://dx.doi.org/10.1101/376277 doi: bioRxiv preprint first posted online Jul. 24, 2018; or activation by modulating their activity (52,54). For example, MALAT1, a known nuclear lncRNA interacts with EZH2, facilitates its occupancy and the H3K27me3 activity on the PRC2 target genes (18), in corroboration to this, we also found that MALAT1 interacts with EZH2 and might facilitate its recruitment on miRNAs regulatory regions.…”

Section: Discussionsupporting

confidence: 71%

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Bhatia

Yadav

Tiwari

et al. 2018

Preprint

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PurposeSerine Peptidase Inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer (PCa) subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in PCa remains largely unknown.Experimental DesignMicroRNA-prediction tools were employed to examine the SPINK1-3’UTR for miRNAs binding. Luciferase reporter assays were performed to confirm the SPINK1-3’UTR binding of shortlisted miR-338-5p/miR-421. Further, miR-338-5p/-421 overexpressing cancer cells (SPINK1-positive) were evaluated for oncogenic properties using cell-based functional assays and mice xenograft model. Global gene expression profiling was performed to unravel the biological pathways altered by miR-338-5p/-421. Immunohistochemistry and RNA in-situ hybridization was carried-out on PCa patients’ tissue microarray for SPINK1 and EZH2 expression respectively. Chromatin immunoprecipitation assay was performed to examine EZH2 occupancy on the miR-338-5p/-421 regulatory regions. Bisulfite sequencing and methylated DNA-immunoprecipitation was performed on PCa cell lines and patients’ specimens.ResultsWe established a critical role of miRNA-338-5p/-421 in post-transcriptional regulation of SPINK1. Ectopic expression of miRNA-338-5p/-421 in SPINK1-positive PCa cells abrogate oncogenic properties including cell-cycle progression, stemness and drug resistance, and show reduced tumor burden and distant metastases in mice model. Importantly, we show SPINK1-positive PCa patients exhibit increased EZH2 expression, suggesting its role in miRNA-338-5p/-421 epigenetic silencing. Furthermore, presence of CpG dinucleotide DNA methylation marks on the regulatory regions of miR-338-5p/-421 in SPINK1-positive PCa cells and patients’ specimens confirms epigenetic silencing.ConclusionOur findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive PCa, while restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis.TRANSLATIONAL IMPACTWe establish a regulatory model involving the functional interplay between SPINK1, miRNA-338-5p/miRNA-421 and EZH2, thereby, revealing hitherto unknown mechanism of SPINK1 up-regulation in SPINK1-positive subtype. Our findings provide a strong rationale for the development of potential therapeutic strategies for SPINK1-positive malignancies. We demonstrate that restoring miRNA-338-5p/miRNA-421 expression using epigenetic drugs including DNMTs inhibitors in combination with HDACs or HKMTs inhibitors or miRNA synthetic mimics in SPINK1-positive prostate cancer abrogate SPINK1-mediated oncogenicity. The major findings of this study will not only advance the prostate cancer field, but will also be valuable for treatment and disease management of other SPINK1-positive malignancies.

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Section: Discussionsupporting

confidence: 71%

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Bhatia

Yadav

Tiwari

et al. 2018

Preprint

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“…A recent study demonstrated that BRG1 binds to a specific lncRNA, termed Myheart, which acts to antagonize BRG1 function (25). The SWI/SNF component hSNF5 interacts with a specific lncRNA termed SChLAP1, which arrests the chromosome association of SWI/SNF complexes (26). Taken together, these findings suggest that some components of SWI/SNF complexes have affinity for lncRNAs.…”

Section: Discussionmentioning

confidence: 54%

SWI/SNF chromatin-remodeling complexes function in noncoding RNA-dependent assembly of nuclear bodies

Kawaguchi

Tanigawa²,

Naganuma

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

140

126

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Paraspeckles are subnuclear structures that form around nuclear paraspeckle assembly transcript 1 (NEAT1) long noncoding RNA (lncRNA). Recently, paraspeckles were shown to be functional nuclear bodies involved in stress responses and the development of specific organs. Paraspeckle formation is initiated by transcription of the NEAT1 chromosomal locus and proceeds in conjunction with NEAT1 lncRNA biogenesis and a subsequent assembly step involving >40 paraspeckle proteins (PSPs). In this study, subunits of SWItch/Sucrose NonFermentable (SWI/SNF) chromatin-remodeling complexes were identified as paraspeckle components that interact with PSPs and NEAT1 lncRNA. EM observations revealed that SWI/SNF complexes were enriched in paraspeckle subdomains depleted of chromatin. Knockdown of SWI/SNF components resulted in paraspeckle disintegration, but mutation of the ATPase domain of the catalytic subunit BRG1 did not affect paraspeckle integrity, indicating that the essential role of SWI/SNF complexes in paraspeckle formation does not require their canonical activity. Knockdown of SWI/SNF complexes barely affected the levels of known essential paraspeckle components, but markedly diminished the interactions between essential PSPs, suggesting that SWI/SNF complexes facilitate organization of the PSP interaction network required for intact paraspeckle assembly. The interactions between SWI/SNF components and essential PSPs were maintained in NEAT1-depleted cells, suggesting that SWI/SNF complexes not only facilitate interactions between PSPs, but also recruit PSPs during paraspeckle assembly. SWI/SNF complexes were also required for Satellite III lncRNA-dependent formation of nuclear stress bodies under heat-shock conditions. Our data suggest the existence of a common mechanism underlying the formation of lncRNA-dependent nuclear body architectures in mammalian cells.chromatin-remodeling complex | long noncoding RNA | nuclear bodies | ribonucleoprotein assembly

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“…In addition, RIP has been also utilized to show SChLAP1 but not other cytoplasmic lncRNAs are immunoprecipitated by SWI/SNF complex 35.…”

Section: Methods Used For Mapping Lncrna Interactionsmentioning

confidence: 99%

State of the art technologies to explore long non‐coding RNAs in cancer

Salehi

Taheri

Azarpira

et al. 2017

J Cellular Molecular Medi

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Long non‐coding RNAs (lncRNAs) comprise a vast repertoire of RNAs playing a wide variety of crucial roles in tissue physiology in a cell‐specific manner. Despite being engaged in myriads of regulatory mechanisms, many lncRNAs have still remained to be assigned any functions. A constellation of experimental techniques including single‐molecule RNA in situ hybridization (sm‐RNA FISH), cross‐linking and immunoprecipitation (CLIP), RNA interference (RNAi), Clustered regularly interspaced short palindromic repeats (CRISPR) and so forth has been employed to shed light on lncRNA cellular localization, structure, interaction networks and functions. Here, we review these and other experimental approaches in common use for identification and characterization of lncRNAs, particularly those involved in different types of cancer, with focus on merits and demerits of each technique.

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

Cited by 622 publications

References 59 publications

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

SWI/SNF chromatin-remodeling complexes function in noncoding RNA-dependent assembly of nuclear bodies

State of the art technologies to explore long non‐coding RNAs in cancer

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