Glutathione S-transferase π-1 (GSTP-1) is a member of the
glutathione S-transferase enzyme superfamily, which catalyzes the conjugation of electrophiles to
glutathione during the process of detoxification. In this study, the epigenetic alterations of GSTP-1 expression in human
colorectal cancers and the underlying mechanisms were investigated. In 10
colon cancer patients, proteomic analysis revealed that expression of GSTP-1
protein was higher in
tumor tissues than in paired adjacent normal tissues. Likewise, in 7 of 10
colon cancer patients, GSTP-1
protein expression was more than 1.5-fold higher in
tumor tissues than in adjacent normal tissues, as determined by western blotting. Immunohistochemical data confirmed that GSTP-1
protein was expressed at higher levels in
colon cancer tissues compared to normal mucosa. GSTP-1
enzyme activity was closely correlated with GSTP-1
protein expression in
colon cancer patients. Consistent with this, GSTP-1
mRNA,
protein and activity levels were higher in the
colorectal cancer cell lines Caco-2, HCT-116, HT-29, SNU-407 and SNU-1033 compared to the normal colon cell line FHC. Methylation-specific PCR results indicated that the high levels of GSTP-1 in human
colorectal cancer cell lines were likely due to the lower degree of promoter methylation in
colon cancer cell lines compared to the normal colon cell line, consistent with findings in
colon cancer patients. Moreover, the levels of specific activator-
protein complexes and histone marks were higher in human
colorectal cancer cells compared to the normal human colon cell line, whereas the repressor
protein complexes exhibited the opposite pattern. Furthermore,
chromatin immunoprecipitation assays demonstrated that expression levels of the
transcription factors AP-1 and SP-1 were correlated with the upregulation of GSTP-1 expression in
colorectal cancer cells. Finally, knockdown of GSTP-1 promoted the sensitivity of SNU-407 cells to the
anticancer agent 5-fluorouracil. These data indicate that GSTP-1 may serve as a clinically useful
biomarker of
colon cancer and a target for anti-
colon cancer drugs.