Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer

Tao Zuo; Ta Ming Liu; Xun Lan; Yu I. Weng; Rulong Shen; Fei Gu; Yi Wen Huang; Sandya Liyanarachchi; Daniel E. Deatherage; Pei Yin Hsu; Cenny Taslim; Bhuvaneswari Ramaswamy; Charles L. Shapiro; Huey Jen L. Lin; Alfred S.L. Cheng; Victor X. Jin; Tim H.M. Huang

doi:10.1158/0008-5472.CAN-10-3573

Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer

Tao Zuo, Ta Ming Liu, Xun Lan, Yu I. Weng, Rulong Shen, Fei Gu, Yi Wen Huang, Sandya Liyanarachchi, Daniel E. Deatherage, Pei Yin Hsu, Cenny Taslim, Bhuvaneswari Ramaswamy, Charles L. Shapiro, Huey Jen L. Lin, Alfred S.L. Cheng, Victor X. Jin, Tim H.M. Huang

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

53 Scopus citations

Abstract

Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future.

Original language	English
Pages (from-to)	1752-1762
Number of pages	11
Journal	Cancer Research
Volume	71
Issue number	5
DOIs	https://doi.org/10.1158/0008-5472.CAN-10-3573
State	Published - 1 Mar 2011
Externally published	Yes

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Zuo, T., Liu, T. M., Lan, X., Weng, Y. I., Shen, R., Gu, F., Huang, Y. W., Liyanarachchi, S., Deatherage, D. E., Hsu, P. Y., Taslim, C., Ramaswamy, B., Shapiro, C. L., Lin, H. J. L., Cheng, A. S. L., Jin, V. X., & Huang, T. H. M. (2011). Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer. Cancer Research, 71(5), 1752-1762. https://doi.org/10.1158/0008-5472.CAN-10-3573

@article{07501d30e0fb45b0a5b4ae381701032f,

title = "Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer",

abstract = "Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future.",

author = "Tao Zuo and Liu, {Ta Ming} and Xun Lan and Weng, {Yu I.} and Rulong Shen and Fei Gu and Huang, {Yi Wen} and Sandya Liyanarachchi and Deatherage, {Daniel E.} and Hsu, {Pei Yin} and Cenny Taslim and Bhuvaneswari Ramaswamy and Shapiro, {Charles L.} and Lin, {Huey Jen L.} and Cheng, {Alfred S.L.} and Jin, {Victor X.} and Huang, {Tim H.M.}",

year = "2011",

month = mar,

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doi = "10.1158/0008-5472.CAN-10-3573",

language = "English",

volume = "71",

pages = "1752--1762",

journal = "Cancer Research",

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Zuo, T, Liu, TM, Lan, X, Weng, YI, Shen, R, Gu, F, Huang, YW, Liyanarachchi, S, Deatherage, DE, Hsu, PY, Taslim, C, Ramaswamy, B, Shapiro, CL, Lin, HJL, Cheng, ASL, Jin, VX & Huang, THM 2011, 'Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer', Cancer Research, vol. 71, no. 5, pp. 1752-1762. https://doi.org/10.1158/0008-5472.CAN-10-3573

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AU - Zuo, Tao

AU - Liu, Ta Ming

AU - Lan, Xun

AU - Weng, Yu I.

AU - Shen, Rulong

AU - Gu, Fei

AU - Huang, Yi Wen

AU - Liyanarachchi, Sandya

AU - Deatherage, Daniel E.

AU - Hsu, Pei Yin

AU - Taslim, Cenny

AU - Ramaswamy, Bhuvaneswari

AU - Shapiro, Charles L.

AU - Lin, Huey Jen L.

AU - Cheng, Alfred S.L.

AU - Jin, Victor X.

AU - Huang, Tim H.M.

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AB - Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future.

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JO - Cancer Research

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Epigenetic silencing mediated through activated PI3K/AKT signaling in breast cancer

Abstract

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