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Vol. 20, Issue 6, 1606-1617, March 15, 2009

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Role of the Tumor Suppressor PTEN in Antioxidant Responsive Element-mediated Transcription and Associated Histone Modifications

Kensuke Sakamoto^*,, Kenta Iwasaki^*, Hiroyuki Sugiyama, and Yoshiaki Tsuji^*

*Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695; and Graduate School of Systems Life Science, Kyushu University, Fukuoka 812-8581, Japan

Submitted July 25, 2008; Revised December 30, 2008; Accepted January 8, 2009
Monitoring Editor: M. Bishr Omary

Coordinated regulation of PI3-kinase (PI3K) and the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) plays a pivotal role in various cell functions. PTEN is deficient in many cancer cells, including Jurkat human leukemia. Here, we demonstrate that the status of PTEN determines cellular susceptibility to oxidative stress through antioxidant-responsive element (ARE)-mediated transcription of detoxification genes. We found that ferritin H transcription was robustly induced in tert-butylhydroquinone (t-BHQ)-treated Jurkat cells via an ARE, and it was due to PTEN deficiency. Chromatin immunoprecipitation assays revealed that p300/CREB-binding protein (CBP) histone acetyltransferases and Nrf2 recruitment to the ARE and Bach1 release were blocked by the PI3K inhibitor LY294002, along with the partial inhibition of Nrf2 nuclear accumulation. Furthermore, acetylations of histone H3 Lys9 and Lys18, and deacetylation of Lys14 were associated with the PI3K-dependent ARE activation. Consistently, PTEN restoration in Jurkat cells inhibited t-BHQ–mediated expression of ferritin H and another ARE-regulated gene NAD(P)H:quinone oxidoreductase 1. Conversely, PTEN knockdown in K562 cells enhanced the response to t-BHQ. The PTEN status under t-BHQ treatment affected hydrogen peroxide-mediated caspase-3 cleavage. The PI3K-dependent ferritin H induction was observed by treatment with other ARE-activating agents ethoxyquin and hemin. Collectively, the status of PTEN determines chromatin modifications leading to ARE activation.

Address correspondence to: Yoshiaki Tsuji (yoshiaki_tsuji{at}ncsu.edu)

Abbreviations used: ARE, antioxidant-responsive element; CBP, CREB-binding protein; ChIP, chromatin immunoprecipitation; LDH, lactate dehydrogenase; NAC, N-acetyl cysteine; NQO1, NAD(P)H:quinone oxidoreductase 1; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; ROS, reactive oxygen species; t-BHQ, tert-butylhydroquinone.

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