TY - JOUR
T1 - LSD1-mediated epigenetic reprogramming drives CENPE expression and prostate cancer progression
AU - Liang, Yi
AU - Ahmed, Musaddeque
AU - Guo, Haiyang
AU - Soares, Fraser
AU - Hua, Junjie T.
AU - Gao, Shuai
AU - Lu, Catherine
AU - Poon, Christine
AU - Han, Wanting
AU - Langstein, Jens
AU - Ekram, Muhammad B.
AU - Li, Brian
AU - Davicioni, Elai
AU - Takhar, Mandeep
AU - Erho, Nicholas
AU - Karnes, R. Jeffrey
AU - Chadwick, Dianne
AU - Van Der Kwast, Theodorus
AU - Boutros, Paul C.
AU - Arrowsmith, Cheryl H.
AU - Feng, Felix Y.
AU - Joshua, Anthony M.
AU - Zoubeidi, Amina
AU - Cai, Changmeng
AU - He, Housheng H.
N1 - Funding Information:
This work was supported by the Princess Margaret Cancer Foundation (886012001223 to H.H. He), the Canada Foundation for Innovation and Ontario Research Fund (CFI32372 to H.H. He), NSERC discovery grant (498706 to H.H. He), WICC Ontario 20th Anniversary Prostate Cancer Innovation Grant of the CCS (703800 to H.H. He) and CIHR operating grant (142246 to H.H. He), Movember Rising Star awards (RS2014-01 to P.C. Boutros and RS2016-1022 to H.H. He) and discovery grant (D2016-1115 to H.H. He) from Prostate Cancer Canada. H.H. He holds an OMIR Early Researcher Award (ER15-11-232), a Terry Fox New Investigator Award (1069), and a CIHR New Investigator Salary Award (147820). P.C. Boutros is supported by a Terry Fox New Investigator Award, a CIHR New Investigator Award, and by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. J. Hua is a CIHR Graduate Student Fellowship recipient (GSD146249).
Publisher Copyright:
2017 AACR.
PY - 2017/10/15
Y1 - 2017/10/15
N2 - Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease.
AB - Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease.
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U2 - 10.1158/0008-5472.CAN-17-0496
DO - 10.1158/0008-5472.CAN-17-0496
M3 - Article
C2 - 28916652
AN - SCOPUS:85031410519
SN - 0008-5472
VL - 77
SP - 5479
EP - 5490
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -