RNA Splicing Factors SRRM3 and SRRM4 Distinguish Molecular Phenotypes of Castration-Resistant Neuroendocrine Prostate Cancer.

TitleRNA Splicing Factors SRRM3 and SRRM4 Distinguish Molecular Phenotypes of Castration-Resistant Neuroendocrine Prostate Cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsLabrecque MP, Brown LG, Coleman IM, Lakely B, Brady NJ, Lee JK, Nguyen HM, Li D, Hanratty B, Haffner MC, Rickman DS, True LD, Lin DW, Lam H-M, Alumkal JJ, Corey E, Nelson PS, Morrissey C
JournalCancer Res
Volume81
Issue18
Pagination4736-4750
Date Published2021 Sep 15
ISSN1538-7445
Abstract

Neuroendocrine (NE) differentiation in metastatic castration-resistant prostate cancer (mCRPC) is an increasingly common clinical feature arising from cellular plasticity. We recently characterized two mCRPC phenotypes with NE features: androgen receptor (AR)-positive NE-positive amphicrine prostate cancer (AMPC) and AR-negative small cell or neuroendocrine prostate cancer (SCNPC). Here, we interrogated the regulation of RE1-silencing transcription factor (REST), a transcriptional repressor of neuronal genes, and elucidated molecular programs driving AMPC and SCNPC biology. Analysis of prostate cancer cell lines, mCRPC specimens, and LuCaP patient-derived xenograft models detected alternative splicing of REST to REST4 and attenuated REST repressor activity in AMPC and SCNPC. The REST locus was also hypermethylated and REST expression was reduced in SCNPC. While serine/arginine repetitive matrix protein 4 (SRRM4) was previously implicated in alternative splicing of REST in mCRPC, we detected SRRM3 expression in REST4-positive, SRRM4-negative AMPC, and SCNPC. In CRPC cell lines, SRRM3 induced alternative splicing of REST to REST4 and exacerbated the expression of REST-repressed genes. Furthermore, SRRM3 and SRRM4 expression defined molecular subsets of AMPC and SCNPC across species and tumor types. Two AMPC phenotypes and three SCNPC phenotypes were characterized, denoted either by REST attenuation and ASCL1 activity or by progressive activation of neuronal transcription factor programs, respectively. These results nominate SRRM3 as the principal REST splicing factor expressed in early NE differentiation and provide a framework to molecularly classify diverse NE phenotypes in mCRPC. SIGNIFICANCE: This study identifies SRRM3 as a key inducer of cellular plasticity in prostate cancer with neuroendocrine features and delineates distinct neuroendocrine phenotypes to inform therapeutic development and precision medicine applications.

DOI10.1158/0008-5472.CAN-21-0307
Alternate JournalCancer Res
PubMed ID34312180
PubMed Central IDPMC8448969
Grant ListP50 CA097186 / CA / NCI NIH HHS / United States
S10 OD028685 / OD / NIH HHS / United States
R01 CA234715 / CA / NCI NIH HHS / United States
P50 CA186786 / CA / NCI NIH HHS / United States
P01 CA163227 / CA / NCI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
R01 CA251245 / CA / NCI NIH HHS / United States
Related Faculty: 
David Rickman, Ph.D. Nicholas Brady, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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