LSD1-mediated epigenetic reprogramming drives CENPE expression and prostate cancer progression

Yi Liang; Musaddeque Ahmed; Haiyang Guo; Fraser Soares; Junjie T. Hua; Shuai Gao; Catherine Lu; Christine Poon; Wanting Han; Jens Langstein; Muhammad B. Ekram; Brian Li; Elai Davicioni; Mandeep Takhar; Nicholas Erho; R. Jeffrey Karnes; Dianne Chadwick; Theodorus Van Der Kwast; Paul C. Boutros; Cheryl H. Arrowsmith; Felix Y. Feng; Anthony M. Joshua; Amina Zoubeidi; Changmeng Cai; Housheng H. He

doi:10.1158/0008-5472.CAN-17-0496

LSD1-mediated epigenetic reprogramming drives CENPE expression and prostate cancer progression

Yi Liang, Musaddeque Ahmed, Haiyang Guo, Fraser Soares, Junjie T. Hua, Shuai Gao, Catherine Lu, Christine Poon, Wanting Han, Jens Langstein, Muhammad B. Ekram, Brian Li, Elai Davicioni, Mandeep Takhar, Nicholas Erho, R. Jeffrey Karnes, Dianne Chadwick, Theodorus Van Der Kwast, Paul C. Boutros, Cheryl H. ArrowsmithFelix Y. Feng, Anthony M. Joshua, Amina Zoubeidi, Changmeng Cai, Housheng H. He

Urology

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	5479-5490
Number of pages	12
Journal	Cancer research
Volume	77
Issue number	20
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-0496
State	Published - Oct 15 2017

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1158/0008-5472.CAN-17-0496

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Liang, Y., Ahmed, M., Guo, H., Soares, F., Hua, J. T., Gao, S., Lu, C., Poon, C., Han, W., Langstein, J., Ekram, M. B., Li, B., Davicioni, E., Takhar, M., Erho, N., Karnes, R. J., Chadwick, D., Van Der Kwast, T., Boutros, P. C., ... He, H. H. (2017). LSD1-mediated epigenetic reprogramming drives CENPE expression and prostate cancer progression. Cancer research, 77(20), 5479-5490. https://doi.org/10.1158/0008-5472.CAN-17-0496

Liang, Y, Ahmed, M, Guo, H, Soares, F, Hua, JT, Gao, S, Lu, C, Poon, C, Han, W, Langstein, J, Ekram, MB, Li, B, Davicioni, E, Takhar, M, Erho, N, Karnes, RJ, Chadwick, D, Van Der Kwast, T, Boutros, PC, Arrowsmith, CH, Feng, FY, Joshua, AM, Zoubeidi, A, Cai, C & He, HH 2017, 'LSD1-mediated epigenetic reprogramming drives CENPE expression and prostate cancer progression', Cancer research, vol. 77, no. 20, pp. 5479-5490. https://doi.org/10.1158/0008-5472.CAN-17-0496

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title = "LSD1-mediated epigenetic reprogramming drives CENPE expression and prostate cancer progression",

abstract = "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.",

author = "Yi Liang and Musaddeque Ahmed and Haiyang Guo and Fraser Soares and Hua, {Junjie T.} and Shuai Gao and Catherine Lu and Christine Poon and Wanting Han and Jens Langstein and Ekram, {Muhammad B.} and Brian Li and Elai Davicioni and Mandeep Takhar and Nicholas Erho and Karnes, {R. Jeffrey} and Dianne Chadwick and {Van Der Kwast}, Theodorus and Boutros, {Paul C.} and Arrowsmith, {Cheryl H.} and Feng, {Felix Y.} and Joshua, {Anthony M.} and Amina Zoubeidi and Changmeng Cai and He, {Housheng H.}",

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doi = "10.1158/0008-5472.CAN-17-0496",

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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.

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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LSD1-mediated epigenetic reprogramming drives CENPE expression and prostate cancer progression

Abstract

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