PCAT-1, a Long Noncoding RNA, Regulates BRCA2 and Controls Homologous Recombination in Cancer

Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long no...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2014-03, Vol.74 (6), p.1651-1660
Main Authors: PRENSNER, John R, WEI CHEN, LOGOTHETIS, Christopher J, ARAUJO, John C, PISTERS, Louis L, TEWARI, Ashutosh K, CANMAN, Christine E, KNUDSEN, Karen E, KITABAYASHI, Naoki, RUBIN, Mark A, DEMICHELIS, Francesca, LAWRENCE, Theodore S, IYER, Matthew K, CHINNAIYAN, Arul M, FENG, Felix Y, QI CAO, TENG MA, SUMIN HAN, SAHU, Anirban, MALIK, Rohit, WILDER-ROMANS, Kari, NAVONE, Nora
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
BRCA2 Protein - genetics
BRCA2 Protein - metabolism
Cell Death - drug effects
Cell Line, Tumor
DNA Damage
Gene Expression Regulation, Neoplastic
Humans
Male
Medical sciences
Mice
Mice, SCID
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Pharmacology. Drug treatments
Phthalazines - pharmacology
Piperazines - pharmacology
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases - metabolism
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Recombinational DNA Repair
RNA Interference
RNA, Long Noncoding - genetics
RNA, Long Noncoding - metabolism
Tumors
Xenograft Model Antitumor Assays
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Summary:Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to small-molecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 3'UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCAness" in sporadic cancers.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-13-3159