TY - JOUR
T1 - SF3B2-mediated RNA splicing drives human prostate cancer progression
AU - Kawamura, Norihiko
AU - Nimura, Keisuke
AU - Saga, Kotaro
AU - Ishibashi, Airi
AU - Kitamura, Koji
AU - Nagano, Hiromichi
AU - Yoshikawa, Yusuke
AU - Ishida, Kyoso
AU - Nonomura, Norio
AU - Arisawa, Mitsuhiro
AU - Luo, Jun
AU - Kaneda, Yasufumi
N1 - Funding Information:
We thank Mayuko Okado and Mieko Watanabe for technical assistance and Dr. Yukio Kawahara for technical advice. This work was supported by Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED under grant number JP19am0101084 and DAICEL, Inc. (to K. Nimura).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/10/15
Y1 - 2019/10/15
N2 - Androgen receptor splice variant-7 (AR-V7) is a constitutively active AR variant implicated in castration-resistant prostate cancers. Here, we show that the RNA splicing factor SF3B2, identified by in silico and CRISPR/Cas9 analyses, is a critical determinant of AR-V7 expression and is correlated with aggressive cancer phenotypes. Transcriptome and PAR-CLIP analyses revealed that SF3B2 controls the splicing of target genes, including AR, to drive aggressive phenotypes. SF3B2-mediated aggressive phenotypes in vivo were reversed by AR-V7 knockout. Pladienolide B, an inhibitor of a splicing modulator of the SF3b complex, suppressed the growth of tumors addicted to high SF3B2 expression. These findings support the idea that alteration of the splicing pattern by high SF3B2 expression is one mechanism underlying prostate cancer progression and therapeutic resistance. This study also provides evidence supporting SF3B2 as a candidate therapeutic target for treating patients with cancer.
AB - Androgen receptor splice variant-7 (AR-V7) is a constitutively active AR variant implicated in castration-resistant prostate cancers. Here, we show that the RNA splicing factor SF3B2, identified by in silico and CRISPR/Cas9 analyses, is a critical determinant of AR-V7 expression and is correlated with aggressive cancer phenotypes. Transcriptome and PAR-CLIP analyses revealed that SF3B2 controls the splicing of target genes, including AR, to drive aggressive phenotypes. SF3B2-mediated aggressive phenotypes in vivo were reversed by AR-V7 knockout. Pladienolide B, an inhibitor of a splicing modulator of the SF3b complex, suppressed the growth of tumors addicted to high SF3B2 expression. These findings support the idea that alteration of the splicing pattern by high SF3B2 expression is one mechanism underlying prostate cancer progression and therapeutic resistance. This study also provides evidence supporting SF3B2 as a candidate therapeutic target for treating patients with cancer.
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U2 - 10.1158/0008-5472.CAN-18-3965
DO - 10.1158/0008-5472.CAN-18-3965
M3 - Article
C2 - 31431456
AN - SCOPUS:85073302815
SN - 0008-5472
VL - 79
SP - 5204
EP - 5217
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -