FKBP3 mediates oxaliplatin resistance in colorectal cancer cells by regulating HDAC2 expression.

ABSTRACT: Colorectal cancer (CRC), a commonly occurring malignant tumor in the gastrointestinal tract, is the third leading cause of cancer?related deaths worldwide. FK506?binding proteins (FKBPs) comprise an immunophilin family that are involved in the carcinogenesis, progression and chemoresistance of cancers, including CRC. FKBP3 (also known as FKBP25) is a nuclear protein that is a member of the FKBP family and is correlated with the activity of histone deacetylase 2 (HDAC2). However, the role of FKBP3 and HDAC2 in oxaliplatin resistance in CRC and the potential molecular mechanisms are still poorly understood. In the present study, the expression of FKBP3, HDAC2 and related?genes was detected by real?time PCR and western blot analysis. Furthermore, cell apoptosis was detected by flow cytometry (FCM). We found high expression of FKBP3 and HDAC2 in CRC tissues. In vitro, primary CRC cells with high expression of FKBP3 and HDAC2 were insensitive to oxaliplatin. Downregulation of FKBP3 significantly increased the sensitivity of primary CRC cells to oxaliplatin, reduced expression of HDAC2, permeability glycoprotein (P?gp) and phosphorylated AKT (p?AKT), and increased expression of phosphatase and tensin homolog (PTEN) and cleaved caspase?3. Accordingly, upregulation of FKBP3 had the opposite effect. Furthermore, downregulation of HDAC2 significantly counteracted FKBP3?induced oxaliplatin resistance in CRC cells. Our data revealed that oxaliplatin resistance in CRC cells is positively associated with FKBP3 and HDAC2 expression, and FKBP3 downregulation could attenuate oxaliplatin resistance in CRC cells by reducing HDAC2 expression and possibly through regulation of the PTEN/AKT pathway.

SUBMITTER: Tong J 

PROVIDER: S-EPMC6718095 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature