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Adenomatous Polyposis Coli Determines Sensitivity to Histone Deacetylase Inhibitor–Induced Apoptosis in Colon Cancer Cells

Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota

Requests for reprints: Bin Guo, Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, ND 58105. Phone: 701-231-5164; Fax: 701-231-8333; E-mail: Bin.Guo{at}ndsu.edu.

Inhibitors of histone deacetylases (HDAC) inhibit malignant cell growth and induce apoptosis through unknown mechanisms. Here, we report that the expression status of adenomatous polyposis coli (APC) protein determines the relative sensitivity of colon cancer cells to HDAC inhibitor–induced apoptosis. HCA-7 cells (expressing wild-type ß-catenin and APC proteins) are more sensitive to apoptosis induced by HDAC inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid than SW620 or HT-29 cells (both expressing mutant APC). When wild-type APC protein was expressed using an inducible expression system, HT-29 cells became sensitive to apoptosis in response to VPA. Conversely, knocking down of endogenous APC protein by small interfering RNA (siRNA) blocked VPA-induced apoptosis in HCA-7 cells. APC mediated VPA-induced apoptosis through down-regulation of survivin. The level of survivin protein decreased in HCA-7 and HT-29/APC cells, but not in SW620 and HT-29/ß-Gal cells after VPA treatment. Whereas knocking down of survivin by siRNA sensitized SW620 cells to VPA-induced apoptosis, overexpression of survivin blocked VPA-induced apoptosis in HCA-7 cells. Down-regulation of survivin transcription occurred through changes in GSK-3ß/ß-catenin/Tcf-4 signaling molecules. VPA also induced proteasome-mediated degradation of survivin protein in HCA-7 cells. Furthermore, we have shown that APC mutation–mediated resistance to apoptosis can be overcome by cotreatment with Flavopiridol, which promotes survivin degradation. These results suggest that APC is a critical determinant of HDAC inhibitor–induced apoptosis in colon cancer cells and survivin is a potential target to enhance apoptotic response to HDAC inhibitors. (Cancer Res 2006; 66(18): 9245-51)