CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: Implications for epigenetic therapy

Liya Ding; Shuai Chen; Ping Liu; Yunqian Pan; Jian Zhong; Kevin M. Regan; Liguo Wang; Chunrong Yu; Anthony Rizzardi; Liang Cheng; Jun Zhang; Stephen C. Schmechel; John C. Cheville; Jan Van Deursen; Donald J. Tindall; Haojie Huang

doi:10.1158/0008-5472.CAN-13-1659

CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: Implications for epigenetic therapy

Liya Ding, Shuai Chen, Ping Liu, Yunqian Pan, Jian Zhong, Kevin M. Regan, Liguo Wang, Chunrong Yu, Anthony Rizzardi, Liang Cheng, Jun Zhang, Stephen C. Schmechel, John C. Cheville, Jan Van Deursen, Donald J. Tindall, Haojie Huang

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

33 Scopus citations

Abstract

Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbp^pc-/-;Pten ^pc+/- mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp^-/-; Pten^+/- and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27 ^KIP1, and p21^CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbp^pc-/-;Pten^pc+/- mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer.

Original language	English (US)
Pages (from-to)	2050-2061
Number of pages	12
Journal	Cancer research
Volume	74
Issue number	7
DOIs	https://doi.org/10.1158/0008-5472.CAN-13-1659
State	Published - Apr 1 2014

ASJC Scopus subject areas

Oncology
Cancer Research

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Ding, L., Chen, S., Liu, P., Pan, Y., Zhong, J., Regan, K. M., Wang, L., Yu, C., Rizzardi, A., Cheng, L., Zhang, J., Schmechel, S. C., Cheville, J. C., Van Deursen, J., Tindall, D. J., & Huang, H. (2014). CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: Implications for epigenetic therapy. Cancer research, 74(7), 2050-2061. https://doi.org/10.1158/0008-5472.CAN-13-1659

Ding, L, Chen, S, Liu, P, Pan, Y, Zhong, J, Regan, KM, Wang, L, Yu, C, Rizzardi, A, Cheng, L, Zhang, J, Schmechel, SC, Cheville, JC, Van Deursen, J, Tindall, DJ & Huang, H 2014, 'CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: Implications for epigenetic therapy', Cancer research, vol. 74, no. 7, pp. 2050-2061. https://doi.org/10.1158/0008-5472.CAN-13-1659

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title = "CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: Implications for epigenetic therapy",

abstract = "Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc-/-;Pten pc+/- mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp-/-; Pten+/- and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27 KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc-/-;Ptenpc+/- mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer.",

author = "Liya Ding and Shuai Chen and Ping Liu and Yunqian Pan and Jian Zhong and Regan, {Kevin M.} and Liguo Wang and Chunrong Yu and Anthony Rizzardi and Liang Cheng and Jun Zhang and Schmechel, {Stephen C.} and Cheville, {John C.} and {Van Deursen}, Jan and Tindall, {Donald J.} and Haojie Huang",

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T2 - Implications for epigenetic therapy

AU - Ding, Liya

AU - Chen, Shuai

AU - Liu, Ping

AU - Pan, Yunqian

AU - Zhong, Jian

AU - Regan, Kevin M.

AU - Wang, Liguo

AU - Yu, Chunrong

AU - Rizzardi, Anthony

AU - Cheng, Liang

AU - Zhang, Jun

AU - Schmechel, Stephen C.

AU - Cheville, John C.

AU - Van Deursen, Jan

AU - Tindall, Donald J.

AU - Huang, Haojie

PY - 2014/4/1

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N2 - Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc-/-;Pten pc+/- mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp-/-; Pten+/- and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27 KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc-/-;Ptenpc+/- mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer.

AB - Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc-/-;Pten pc+/- mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp-/-; Pten+/- and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27 KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc-/-;Ptenpc+/- mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer.

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CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: Implications for epigenetic therapy

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