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Novel Small Molecules Regulating The Histone Marking, AR Signaling, And AKT Inhibition In Prostate Cancer
Huang, Po-Hsien

2010, Doctor of Philosophy, Ohio State University, Pharmacy.

The dissertation focuses on two themes 1) the elucidation of histone modifications by histone deacetylase inhibitors, and 2) the effect of vitamin E derivatives on androgen receptor signaling and the Akt inhibition. The first project is to identify a novel pathway by which AR42 (also known as OSU-HDAC42) and other HDAC inhibitors differentially modulate the abundance of histone H3 lysine 4 (H3K4) modification and focuses on determining the role of histone deacetylase (HDAC) in the process of tumorigenesis in prostate cancer.


We have found that a novel HDAC inhibitor, AR42, blocks the progression of PIN to adenocarcinoma in the TRAMP model, and we hypothesize that the epigenetic reprogramming incurred by AR42, inhibits tumor progression. We investigated the effect of AR42 on the enrichment of H3K4 methylation and the underlying mechanism for this crosstalk. The results showed that HDAC inhibition by AR42 and other HDAC inhibitors leads to suppression of Sp1 and its downstream histone H3 lysine 4 (H3K4) demethylases. Transfection with the HDAC shRNA plasmids could mimic this process. The effect of HDAC silencing by these agents also leads to upregulation of KLF4 and E-cadherin, suggesting that HDAC plays a significant role in tumorigenesis through epigenetic silencing of tumor suppressor genes. This project established the functional crosstalk among histone acetylation,methylation in the process of tumorigenesis through the HDAC-Sp1 signaling.


The second project focused on delineating novel mechanisms underlying the antitumor effects of α-tocopherol (vitamin E) and its succinate derivatives, as well as the side-chain truncated derivatives. The effect of α-tocopherol succinate on the suppression of tumor growth by targeting the PP2A-JNK-Sp1 signaling axis, which has provided the molecular basis for developing novel PP2A-activating agents. With the effects of α-tocopherol on Akt inhibition, we aim to elucidate the mechanism and to validate the drug target in the PI3K-Akt pathway. We have found that the exposure of LNCaP cells to α-VE5 led to Akt dephosphorylation and apoptotic cell death without changing the cellular levels of PIP3. Our results showed that α-tocopherol and its truncated derivatives recruitment PH domain-containing proteins to the non-raft domain of cell membrane, including Akt and PHLPP, leading to the Ser473Akt-specific dephosphorylation.


This study provided not only the correlation between class I HDACs and H3K4 demethylases via Sp1 as a functional link, but also a novel mechanism of Akt dephosphorylation through a PH domain-dependent co-recruitment of Akt and PHLPP by which tocopheryl derivatives induce apoptotic cell death.

Ching-Shih Chen, Ph.D. (Advisor)
Robert Brueggemeier, Ph.D. (Other)
John Byrd, M.D. (Other)
Chenglong Li, Ph.D. (Other)
123 p.

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Huang, P. (2010). Novel Small Molecules Regulating The Histone Marking, AR Signaling, And AKT Inhibition In Prostate Cancer. (Electronic Thesis or Dissertation). Retrieved from https://etd.ohiolink.edu/

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Huang, Po-Hsien. "Novel Small Molecules Regulating The Histone Marking, AR Signaling, And AKT Inhibition In Prostate Cancer." Electronic Thesis or Dissertation. Ohio State University, 2010. OhioLINK Electronic Theses and Dissertations Center. 19 Nov 2018.

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Huang, Po-Hsien "Novel Small Molecules Regulating The Histone Marking, AR Signaling, And AKT Inhibition In Prostate Cancer." Electronic Thesis or Dissertation. Ohio State University, 2010. https://etd.ohiolink.edu/

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