Histone deacetylases (HDACs) are key players in gene regulation and proven targets for cancer therapy. Inhibition of HDAC activity arrests cancer cell growth and promotes cell death. Because the current HDAC inhibitors are designed to target the conserved catalytic site, their capacity for distinguishing different isoforms of HDA is inherently limited. These pan-HDAC inhibitors produce profound side effects that have limited their use. Recent studies have shown that HDAC3 plays a unique role in gene regulation and tumorigenesis, and that its overexpression in multiple cancer types is correlated with poor survival and prognosis. Depletion of HDAC3 arrests tumor proliferation, induces necrosis, and improves survival in mouse models. The phenotypic changes of cells upon depletion of HDAC3 suggest that HDAC3 is responsible for most of the beneficial effects of the HDAC inhibitors currently used in clinical trials. It is thus important to develop approaches that can specifically inhibit HDAC3 function in cancer cells. This application is focused on how HDAC3 is activated and stabilized by its specific interacting proteins, the nuclear receptor corepressors (CoRs). This study is significant because understanding the unique mechanism of HDAC3 activation and degradation carries the promise to specifically inactivate HDAC3 in cancer. This study is innovative because we have recently discovered novel regulatory mechanisms underlying HDAC3 activation and degradation via proteasomal pathways. HDAC3 differs from other HDACs in that it must undergo an activation step to become a functional enzyme. This activation entails the binding of HDAC3 to CoRs. Prior to activation, the inactive free HDAC3 is tightly associated with Hsc70 and TRiC chaperones. These chaperones are released from the mature active form of the HDAC3-CoR complex, suggesting a role for chaperones in the inhibition of HDAC3 activity. My lab has recently shown that the free chaperone-associated HDAC3 is also unstable and subject to rapid turnover by proteasomal pathways. Importantly, we found that the unique C- terminus of HDAC3 plays a previously unrecognized role in coupling CoR binding, chaperone dismissal, and subsequent activation of HDAC3. These results provide evidence for the existence of an inactive and unstable intermediate HDAC3 complex containing both CoRs and Hsc70 chaperones. We hypothesize that the transition from this intermediate complex to a fully active and stable HDAC3-CoR complex requires a conformational change in HDAC3 resulting from the interplay between CoR and the C-terminus of HDAC3. We will further test this hypothesis by delineating the mechanism of CoR- and HDAC3 C-terminus-dependent activation of HDAC3 and identifying factors that mediate proteasomal degradation of HDAC3. A better understanding of the specific mechanisms underlying the activation and degradation of HDAC3 should provide insight for the development of new drugs to specifically target HDAC3 in cancer. Such drugs are expected to significantly improve clinical outcomes and may have a broader use in the treatment of various types of cancers and leukemias.

Public Health Relevance

Although histone deacetylase 3 (HDAC3) is the key target of the HDAC inhibition therapy for cancer, these inhibitors affect other HDACs nonspecifically and have profound side effects that limit their use for treatment. Understanding the unique mechanisms of HDAC3 activation and turnover should facilitate the development of HDAC3-specific drugs to improve cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA178513-01A1
Application #
8755275
Study Section
Special Emphasis Panel (ZCA1-SRLB-1 (M1))
Program Officer
Okano, Paul
Project Start
2014-06-18
Project End
2016-05-31
Budget Start
2014-06-18
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$197,708
Indirect Cost
$67,208
Name
Saint Louis University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103