Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer

Adam G. Sowalsky, Zheng Xia, Liguo Wang, Hao Zhao, Shaoyong Chen, Glenn J. Bubley, Steven P. Balk, Wei Li

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Men with metastatic prostate cancer who are treated with androgen deprivation therapies (ADT) usually relapse within 2 to 3 years with disease that is termed castration-resistant prostate cancer (CRPC). To identify the mechanism that drives these advanced tumors, paired-end RNA-sequencing (RNA-seq) was performed on a panel of CRPC bone marrow biopsy specimens. From this genome-wide approach, mutations were found in a series of genes with prostate cancer relevance, including AR, NCOR1, KDM3A, KDM4A, CHD1, SETD5, SETD7, INPP4B, RASGRP3, RASA1, TP53BP1, and CDH1, and a novel SND1:BRAF gene fusion. Among the most highly expressed transcripts were 10 noncoding RNAs (ncRNAs), including MALAT1 and PABPC1, which are involved in RNA processing. Notably, a high percentage of sequence reads mapped to introns, which were determined to be the result of incomplete splicing at canonical splice junctions. Using quantitative PCR (qPCR), a series of genes (AR, KLK2, KLK3, STEAP2, CPSF6, and CDK19) were confirmed to have a greater proportion of unspliced RNA in CRPC specimens than in normal prostate epithelium, untreated primary prostate cancer, and cultured prostate cancer cells. This inefficient coupling of transcription and mRNA splicing suggests an overall increase in transcription or defect in splicing. Implications: Inefficient splicing in advanced prostate cancer provides a selective advantage through effects on microRNA networks but may render tumors vulnerable to agents that suppress rate-limiting steps in splicing.

Original languageEnglish (US)
Pages (from-to)98-106
Number of pages9
JournalMolecular Cancer Research
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Castration
Transcriptome
Prostatic Neoplasms
Messenger RNA
RNA
RNA Sequence Analysis
Bone Neoplasms
Untranslated RNA
Gene Fusion
MicroRNAs
Introns
Androgens
Genes
Prostate
Neoplasms
Epithelium
Bone Marrow
Genome
Biopsy
Recurrence

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer. / Sowalsky, Adam G.; Xia, Zheng; Wang, Liguo; Zhao, Hao; Chen, Shaoyong; Bubley, Glenn J.; Balk, Steven P.; Li, Wei.

In: Molecular Cancer Research, Vol. 13, No. 1, 01.01.2015, p. 98-106.

Research output: Contribution to journalArticle

Sowalsky, Adam G. ; Xia, Zheng ; Wang, Liguo ; Zhao, Hao ; Chen, Shaoyong ; Bubley, Glenn J. ; Balk, Steven P. ; Li, Wei. / Whole transcriptome sequencing reveals extensive unspliced mRNA in metastatic castration-resistant prostate cancer. In: Molecular Cancer Research. 2015 ; Vol. 13, No. 1. pp. 98-106.
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