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 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.
Authors' Affiliations: Michigan Center for Translational Pathology; Departments of Pathology, Radiation Oncology, Internal Medicine, Pharmacology, and Urology; Comprehensive Cancer Center; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan; Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas; Department of Urology, Institute of Prostate Cancer and LeFrak Center For Robotic Surgery; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York Presbyterian Hospitals, New York, New York; Departments of Cancer Biology, Urology, and Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania; and Centre for Integrative Biology, University of Trento, Trento, Italy.
John R
JR
Prensner
Wei
W
Chen
Matthew K
MK
Iyer
Qi
Q
Cao
Teng
T
Ma
Sumin
S
Han
Anirban
A
Sahu
Rohit
R
Malik
Kari
K
Wilder-Romans
Nora
N
Navone
Christopher J
CJ
Logothetis
John C
JC
Araujo
Louis L
LL
Pisters
Ashutosh K
AK
Tewari
Christine E
CE
Canman
Karen E
KE
Knudsen
Naoki
N
Kitabayashi
Mark A
MA
Rubin
Francesca
F
Demichelis
Theodore S
TS
Lawrence
Arul M
AM
Chinnaiyan
Felix Y
FY
Feng
D020413:3' Untranslated Regions; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D059767:Recombinational DNA Repair; D023041:Xenograft Model Antitumor Assays
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C588212:PCAT-1 lncRNA, human; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D062085:RNA, Long Noncoding; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib