Elucidating the mechanisms by which cancer cells maintain viability through control of cell cycle-regulated events and checkpoints could identify novel therapeutic targets. We have previously discovered that human histone deacetylase 4 (HDAC4) is a component of the DNA damage response that contributes to mediating G2/M checkpoints, and promotes the viability of cancer cells. While those findings were the first to link a Class II HDAC to the DNA damage response and identified a novel pathway which could be targeted with HDAC-inhibitors to enhance anticancer treatment, the molecular mechanisms by which HDAC4 promoted cell survival remained to be identified. We have now found that during the progression into mitosis HDAC4 deacetylates the core histones and mediates the activation of BubR1, a key component of the mitotic spindle checkpoint. Silencing of HDAC4 via RNA interference or treatment with a histone deacetylase inhibitor blocked phosphorylation of BubR1 and histone H3, and negated mitotic arrest after exposure to nocodazole. We believe these effects of HDAC4 are mechanistically linked and together influence cancer cell viability. We have further identified mechanisms controlling HDAC4 expression. Consistent with vital activities during G2/M, expression of HDAC4 is maximal at that part of the cell-cycle and after DNA damage, possibly driven by a combination of decreased proteolysisldegradation, Specificity factor 1 (Sp1) activation, and increased translational efficiency. We propose here a plan of attack combining cytological, biochemical, pharmacological and genetic approaches to clarify the specific mechanisms by which HDAC4 and histone deacetylation affect the activity of components of the cellular machinery mediating mitotic checkpoints and progression, and the conditions leading to maximally decreased cancer cell viability (Specific Aim 1). We will also investigate the mechanisms controlling expression of HDAC4, including the cell-cycle and checkpoint specificity of Spl activation, the nature of untranslated mRNA sequences mediating increased translational efficiency of HDAC4, and the protein sequences which determine HDAC4 stability (Specific Aim 2). These investigations together will enable us to test a model of HDAC4 expression and function, in which HDAC4 deacetylates core histones during progression into mitosis, promotes the activity of components mediating cell-cycle checkpoints, which in turn allows continued expression of HDAC4 until conditions allow successful mitotic progression. When aspects of this unique and vital feedback loop are interrupted, cellular death ensues.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107956-03
Application #
7027112
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Pelroy, Richard
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$243,771
Indirect Cost
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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