Histone deacetylase inhibitors (HDACis) are a promising new class of anticancer drugs. Two HDACis are licensed by the United States FDA for the treatment of advanced cutaneous T-cell lymphoma. Although clinical trials with HDACis as monotherapy in solid tumors have not been successful, HDACi shows promise in combination therapy for patients with recurrent metastatic lung cancer, suggesting that the full therapeutic potential of current HDACis will probably be best realized through a combination with other anticancer agents. However, currently there is little information to direct the clinical use of HDACi in combination with other agents. As colorectal cancer (CRC) remains an essentially incurable disease, it is critical to identify mechanism of HDACi resistance that can lead to combination strategies that increase HDACi therapeutic potential in CRC. The overall goal of this project is to uncover the HDAC mechanism responsible for the limited efficacy of HDACi treatment in colorectal cancer. There are 18 HDACs in humans and these different HDACs are not redundant in their function. In CRC, one of the most cancer relevant HDACs is HDAC2. We have found that in CRC cells, HDAC2 knockdown enhances the anti-tumor effect of SAHA, whereas overexpression of HDAC2 confers resistance to SAHA treatment. These findings strongly suggest that HDAC2 influences HDACi sensitivity and contributes to refractoriness to HDACi therapy in CRC cells. But the underlying mechanism by which HDAC2 works remains undefined. Clinical evidence suggests that HDACi refractoriness may involve mechanisms independent of deacetylase inhibition. Intriguingly, we have discovered that HDAC2 possesses a deacetylase-independent sumoylation-promoting activity and promotes sumoylation of Gsk3? (a key component of Wnt signaling). Based on our preliminary results, we hypothesize that HDAC2 sumoylation-promoting activity contributes to HDACi refractoriness in CRC cells by upregulating the Wnt/?-catenin pathway through enhancing Gsk3? sumoylation. In this proposal, we will determine the role of the Wnt/?-catenin pathway in HDAC2-mediated refractoriness in HDACi therapy. We will then validate the role of HDAC2 sumoylation-promoting activity in HDACi sensitivity of CRC cells. Finally, we will dissect how HDAC2 upregulates the Wnt/?-catenin pathway through enhancing Gsk3? sumoylation. The successful completion of this proposed study could reveal a possible cause of insensitivity to HDACi treatment in CRC.

Public Health Relevance

A clear understanding of underlying HDAC biology that renders HDACi resistance in a given tumor type, is crucial for developing strategies to overcome HDACi resistance in that particular type of tumor. This application seeks to uncover how HDAC2 contributes to refractoriness to HDACi therapy in colorectal cancer. The information gained from this study could lead to identification of new drug combinations and more rationally designed future trials. By offering a novel concept of and new criteria for HDAC inhibition, our study could provide a framework for the development of HDAC2-specific HDACi.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166197-02
Application #
8511592
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Arya, Suresh
Project Start
2012-07-16
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$297,452
Indirect Cost
$102,402
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Gao, Chenxi; Xiao, Gutian; Hu, Jing (2014) Regulation of Wnt/?-catenin signaling by posttranslational modifications. Cell Biosci 4:13
Gao, Chenxi; Chen, Guangming; Romero, Guillermo et al. (2014) Induction of Gsk3?-?-TrCP interaction is required for late phase stabilization of ?-catenin in canonical Wnt signaling. J Biol Chem 289:7099-108