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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

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

Tong Jiafeng J Shen Ying Y Chen Xi X Wang Renjie R Hu Ye Y Zhang Xu X Zhang Zhenghua Z Han Li L

Oncology reports 20190802 4

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 FKBP ...[more]

PMID: 31524278

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Project description:Colorectal cancer is a major contributor to the worldwide prevalence of cancer-related deaths. Metastasis and chemoresistance are the two main causes for colorectal cancer treatment failure, and thus, high mortality. Calmodulin-binding transcription activator 1 (CAMTA1) is involved in tumor growth and development, but its mechanisms of action in the development of colorectal cancer and chemoresistance are poorly understood. Here, we report that Camta1 is a tumor suppressor. Immunohistochemical staining and western blotting analyses of normal and colorectal cancer tissues showed a significantly low expression of Camta1 expression in colorectal cancer tissues, when compared to adjacent normal tissues. In functional in vitro experiments, we observed that Camta1 overexpression significantly decreased the proliferation and invasion capacity of SW620 and SW480 cells, whereas Camta1 knockdown displayed a significant increase in the proliferative and invasive ability of these cells. Subsequently, we examined the effects of Camta1 overexpression and knockdown on the resistance of colorectal cancer cells to oxaliplatin, a common chemotherapeutic drug. Interestingly, the sensitivity of Camta1-overexpressed cells to oxaliplatin was increased, whereas that of Camta1-silenced cells to the same chemotherapeutic drug was decreased. Furthermore, Camta1 knockdown upregulated nuclear factor of activated T cells, cytoplasmic 4 (Nfatc4) mRNA, and protein levels in colorectal cancer cells and downregulated the phosphorylated NFATc4 level. By contrast, Nfatc4 knockdown reversed the resistance of colorectal cancer cells to oxaliplatin caused by Camta1 knockdown. In addition, we show that protein phosphatase 3 catalytic subunit alpha (PPP3CA) is essential for the expression and phosphorylation of NFATc4 caused by Camta1 knockdown, as well as the proliferation, invasion, and chemoresistance of colorectal cancer cells. We show that PPP3CA and CAMTA1 competitively bind to NFATc4, and Camta1 knockdown promotes the dephosphorylation of PPP3CA and suppresses the phosphorylation of NFATc4. To verify the role of CAMTA1 in oxaliplatin resistance in colorectal cancer, we established a xenograft mouse model and show agreement between in vitro and in vivo results.

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

Publications

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

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