SIRT2 deacetylates and decreases the expression of FOXM1 in colon cancer

New FOXM1‐specific inhibitors with the potential to be used for therapeutic purposes are under extensive research. We hypothesized that deacetylation of FOXM1 would decrease protein expression, thus providing novel therapeutic management of colon cancers. Immunostaining was used to determine FOXM1 and SIRT2 expressions in human colon cancer tissue microarrays (n = 90) from Stage I to Stage IV. SIRT2‐FOXM1 interaction was evaluated in colon cancer cells using immunoprecipitation. Deacetylation of FOXM1 via SIRT2 was determined using in vitro deacetylation assays. FOXM1 could be hyper‐acetylated when p300 and pCAF histone acetyltransferases were administered alongside deacetylase inhibitors. We detected that SIRT2 and FOXM1 physically interacted, and SIRT2 deacetylated FOXM1 in vitro. SIRT2 overexpression led to a significant decrease while knockdown of SIRT2 increased the FOXM1 expression in HCT116 human colon carcinoma cells. In the analysis of 90 human colorectal cancer samples, high SIRT2 expression was observed in about 49% of colorectal cancer, intermediate in 29%, and low or no staining in 22%. Strong SIRT2 expression was found to be negatively associated with the FOXM1 staining in our clinical cohort. This study reveals a molecular interaction and association between SIRT2 and FOXM1 expression in colon cancer cell lines and human colon cancer samples, and suggests that targeting SIRT2 activity using small molecule modulators may be a promising therapeutic approach for colorectal cancer. SIRT2‐FOXM1 interaction in colon cancer. SIRT2 and FOXM1 physically interacted and SIRT2 deacetylated FOXM1 in vitro. Strong SIRT2 expression was negatively associated with FOXM1 staining in a human colon carcinoma tissue microarray. Resveratrol, berberine, and quercetin reduced FOXM1 expression in colon cancer cells. Highlights Upregulation of FOXM1 may be an early molecular signal required for cancer SIRT2 and FOXM1 physically interacted, and SIRT2 deacetylated FOXM1 in vitro Strong SIRT2 expression was negatively associated with the FOXM1 staining in the TMA Resveratrol, berberine and quercetin decreased FOXM1 expression in colorectal cancer cells