Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding

Deguan Lv, Feng Jia, Yanli Hou, Youzhou Sang, Angel A Alvarez, Weiwei Zhang, Wei Qiang Gao, Bo Hu, Shi-Yuan Cheng, Jianwei Ge*, Yanxin Li, Haizhong Feng

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity–deficient mutants or TRIM24 mutants lacking H3K23ac-bind-ing sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment.

Original languageEnglish (US)
Pages (from-to)6190-6201
Number of pages12
JournalCancer Research
Volume77
Issue number22
DOIs
StatePublished - Nov 15 2017

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Histone Acetyltransferases
Glioblastoma
Phosphatidylinositol 3-Kinases
Up-Regulation
Histone Code
Cell Proliferation
Acetyltransferases
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Cytoplasmic and Nuclear Receptors
Growth
Heterografts
Glioma
Histones
Lysine
Chromatin
Cell Movement
Neoplasms
Carrier Proteins
Carcinogenesis
Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lv, Deguan ; Jia, Feng ; Hou, Yanli ; Sang, Youzhou ; Alvarez, Angel A ; Zhang, Weiwei ; Gao, Wei Qiang ; Hu, Bo ; Cheng, Shi-Yuan ; Ge, Jianwei ; Li, Yanxin ; Feng, Haizhong. / Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding. In: Cancer Research. 2017 ; Vol. 77, No. 22. pp. 6190-6201.
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abstract = "Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity–deficient mutants or TRIM24 mutants lacking H3K23ac-bind-ing sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment.",
author = "Deguan Lv and Feng Jia and Yanli Hou and Youzhou Sang and Alvarez, {Angel A} and Weiwei Zhang and Gao, {Wei Qiang} and Bo Hu and Shi-Yuan Cheng and Jianwei Ge and Yanxin Li and Haizhong Feng",
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Lv, D, Jia, F, Hou, Y, Sang, Y, Alvarez, AA, Zhang, W, Gao, WQ, Hu, B, Cheng, S-Y, Ge, J, Li, Y & Feng, H 2017, 'Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding', Cancer Research, vol. 77, no. 22, pp. 6190-6201. https://doi.org/10.1158/0008-5472.CAN-17-1388

Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding. / Lv, Deguan; Jia, Feng; Hou, Yanli; Sang, Youzhou; Alvarez, Angel A; Zhang, Weiwei; Gao, Wei Qiang; Hu, Bo; Cheng, Shi-Yuan; Ge, Jianwei; Li, Yanxin; Feng, Haizhong.

In: Cancer Research, Vol. 77, No. 22, 15.11.2017, p. 6190-6201.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding

AU - Lv, Deguan

AU - Jia, Feng

AU - Hou, Yanli

AU - Sang, Youzhou

AU - Alvarez, Angel A

AU - Zhang, Weiwei

AU - Gao, Wei Qiang

AU - Hu, Bo

AU - Cheng, Shi-Yuan

AU - Ge, Jianwei

AU - Li, Yanxin

AU - Feng, Haizhong

PY - 2017/11/15

Y1 - 2017/11/15

N2 - Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity–deficient mutants or TRIM24 mutants lacking H3K23ac-bind-ing sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment.

AB - Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity–deficient mutants or TRIM24 mutants lacking H3K23ac-bind-ing sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment.

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