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

Tong,Jiafeng; Shen,Ying; Chen,Xi; Wang,Renjie; Hu,Ye; Zhang,Xu; Zhang,Zhenghua; Han,Li

doi:10.3892/or.2019.7259

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

Authors:
- Jiafeng Tong
- Ying Shen
- Xi Chen
- Renjie Wang
- Ye Hu
- Xu Zhang
- Zhenghua Zhang
- Li Han
View Affiliations

Affiliations: Department of Traditional Chinese Medicine, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China, Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China, Department of Oncology, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China, Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200030, P.R. China, Department of Oncology, Jing'an District Central Hospital of Shanghai (Huashan Hospital,Fudan University, Jing'an Branch), Shanghai 200040, P.R. China
Published online on: August 2, 2019 https://doi.org/10.3892/or.2019.7259
Pages: 1404-1412
Copyright: © Tong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Ung L, Lam KY, Morris DL and Chua TC: Tissue-based biomarkers predicting outcomes in metastatic colorectal cancer: a review. Clin Transl Oncol. 16:425–435. 2014. View Article : Google Scholar : PubMed/NCBI
2	Sostres C, Gargallo CJ and Lanas A: Aspirin, cyclooxygenase inhibition and colorectal cancer. World J Gastrointest Pharmacol Ther. 5:40–49. 2014. View Article : Google Scholar : PubMed/NCBI
3	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
4	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
5	Overman MJ, Morris V, Moinova H, Manyam G, Ensor J, Lee MS, Eng C, Kee B, Fogelman D, Shroff RT, et al: Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: Evaluation of circulating methylated vimentin. Oncotarget. 7:67495–67506. 2016. View Article : Google Scholar : PubMed/NCBI
6	Meyerhardt JA and Mayer RJ: Systemic therapy for colorectal cancer. N Engl J Med. 352:476–487. 2005. View Article : Google Scholar : PubMed/NCBI
7	Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 7:573–584. 2007. View Article : Google Scholar : PubMed/NCBI
8	Koul D, Shen R, Bergh S, Sheng X, Shishodia S, Lafortune TA, Lu Y, de Groot JF, Mills GB and Yung WK: Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma. Mol Cancer Ther. 5:637–644. 2006. View Article : Google Scholar : PubMed/NCBI
9	Xiong F and Chen J: Effect of miR-3651 on proliferation, apoptosis and expression of PTEN in colon cancer cells. Chin Clin Oncol. 22:865–868. 2017.
10	Liang YF, Jian-Bo R, Wang LM, Chen C, Kang DP, Lin BH, Chai XX, Zeng JC and Pathology DO: Expression and clinical significance of PTEN in colon cancer. China Tropical Med. 15:966–969. 2015.
11	He C, Dong X, Zhai B, Jiang X, Dong D, Li B, Jiang H, Xu S and Sun X: MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway. Oncotarget. 6:28867–28881. 2015. View Article : Google Scholar : PubMed/NCBI
12	Li J, Zhang Y, Zhao J, Kong F and Chen Y: Overexpression of miR-22 reverses paclitaxel-induced chemoresistance through activation of PTEN signaling in p53-mutated colon cancer cells. Mol Cell Biochem. 357:31–38. 2011. View Article : Google Scholar : PubMed/NCBI
13	Solassol J, Mange A and Maudelonde T: FKBP family proteins as promising new biomarkers for cancer. Curr Opin Pharmacol. 11:320–325. 2011. View Article : Google Scholar : PubMed/NCBI
14	Mukaide H, Adachi Y, Taketani S, Iwasaki M, Koi-Kekiriyama N, Shigematsu A, Shi M, Yanai S, Yoshioka K, Kamiyama Y and Ikehara S: FKBP51 expressed by both normal epithelial cells and adenocarcinoma of colon suppresses proliferation of colorectal adenocarcinoma. Cancer Invest. 26:385–390. 2008. View Article : Google Scholar : PubMed/NCBI
15	Li L, Lou Z and Wang L: The role of FKBP5 in cancer aetiology and chemoresistance. Br J Cancer. 104:19–23. 2011. View Article : Google Scholar : PubMed/NCBI
16	Luo K, Li Y, Yin Y, Lei L, Wu C, Chen Y, Nowsheen S, Qi H, Zhang L, Lou Z and Yuan J: USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling. EMBO J. 36:1434–1446. 2017. View Article : Google Scholar : PubMed/NCBI
17	Ochocka AM, Kampanis P, Nicol S, Allende-Vega N, Cox M, Marcar L, Milne D, Fuller-Pace F and Meek D: FKBP25, a novel regulator of the p53 pathway, induces the degradation of MDM2 and activation of p53. FEBS Lett. 583:621–626. 2009. View Article : Google Scholar : PubMed/NCBI
18	Yang WM, Yao YL and Seto E: The FK506-binding protein 25 functionally associates with histone deacetylases and with transcription factor YY1. EMBO J. 20:4814–4825. 2001. View Article : Google Scholar : PubMed/NCBI
19	Oiso H, Furukawa N, Suefuji M, Shimoda S, Ito A, Furumai R, Nakagawa J, Yoshida M, Nishino N and Araki E: The role of class I histone deacetylase (HDAC) on gluconeogenesis in liver. Biochem Biophys Res Commun. 404:166–172. 2011. View Article : Google Scholar : PubMed/NCBI
20	Jeong JB and Lee SH: Protocatechualdehyde possesses anti- cancer activity through downregulating cyclin D1 and HDAC2 in human colorectal cancer cells. Biochem Biophys Res Commun. 430:381–386. 2013. View Article : Google Scholar : PubMed/NCBI
21	Zhang H, Zhao B, Huang C, Meng XM, Bian EB and Li J: Melittin restores PTEN expression by down-regulating HDAC2 in human hepatocelluar carcinoma HepG2 cells. PLoS One. 9:e955202014. View Article : Google Scholar : PubMed/NCBI
22	Zhu W, Li Z, Xiong L, Yu X, Chen X and Lin Q: FKBP3 promotes proliferation of non-small cell lung cancer cells through regulating Sp1/HDAC2/p27. Theranostics. 7:3078–3089. 2017. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Hong JY, Kang B, Kim A, Hwang S, Ahn J, Lee S, Kim J, Park JH and Cheon DS: Development of a highly sensitive real-time one step RT-PCR combined complementary locked primer technology and conjugated minor groove binder probe. Virol J. 8:3302011. View Article : Google Scholar : PubMed/NCBI
25	Xiong H, Hong J, Du W, Lin YW, Ren LL, Wang YC, Su WY, Wang JL, Cui Y, Wang ZH and Fang JY: Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J Biol Chem. 287:5819–5832. 2012. View Article : Google Scholar : PubMed/NCBI
26	Virag P, Brie I, Fischer-Fodor E, Perde-Schrepler M, Tatomir C, Balacescu O, Irimie A and Postescu ID: Assessment of cytotoxicity, apoptosis and DNA damages in Colo320 colorectal cancer cells selected for oxaliplatin resistance. Cell Biochem Funct. 29:351–355. 2011. View Article : Google Scholar : PubMed/NCBI
27	Cohen GM: Caspases: The executioners of apoptosis. Biochem J. 326:1–16. 1997. View Article : Google Scholar : PubMed/NCBI
28	Gao G and Dou QP: G(1) phase-dependent expression of bcl-2 mRNA and protein correlates with chemoresistance of human cancer cells. Mol Pharmacol. 58:1001–1010. 2000. View Article : Google Scholar : PubMed/NCBI
29	Lee MS, Jeong MH, Lee HW, Han HJ, Ko A, Hewitt SM, Kim JH, Chun KH, Chung JY, Lee C, et al: PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis. Nat Commun. 6:77692015. View Article : Google Scholar : PubMed/NCBI
30	Salmena L, Carracedo A and Pandolfi PP: Tenets of PTEN tumor suppression. Cell. 133:403–414. 2008. View Article : Google Scholar : PubMed/NCBI
31	Davies MA, Lu Y, Sano T, Fang X, Tang P, Lapushin R, Koul D, Bookstein R, Stokoe D, Yung WK, et al: Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits akt activation and induces anoikis. Cancer Res. 58:5285–5290. 1998.PubMed/NCBI
32	Mehrian-Shai R, Chen CD, Shi T, Horvath S, Nelson SF, Reichardt JK and Sawyers CL: Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci USA. 104:5563–5568. 2007. View Article : Google Scholar : PubMed/NCBI
33	Choi BH and Yoon HS: FKBP38-Bcl-2 interaction: A novel link to chemoresistance. Curr Opin Pharmacol. 11:354–359. 2011. View Article : Google Scholar : PubMed/NCBI
34	Ma D, Bai X, Zou H, Lai Y and Jiang Y: Rheb GTPase controls apoptosis by regulating interaction of FKBP38 with Bcl-2 and Bcl-XL. J Biol Chem. 285:8621–8627. 2010. View Article : Google Scholar : PubMed/NCBI
35	Krämer OH, Knauer SK, Zimmermann D, Stauber RH and Heinzel T: Histone deacetylase inhibitors and hydroxyurea modulate the cell cycle and cooperatively induce apoptosis. Oncogene. 27:732–740. 2008. View Article : Google Scholar : PubMed/NCBI
36	Jung KH, Noh JH, Kim JK, Eun JW, Bae HJ, Xie HJ, Chang YG, Kim MG, Park H, Lee JY and Nam SW: HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins. J Cell Biochem. 113:2167–2177. 2012. View Article : Google Scholar : PubMed/NCBI
37	Wang X, Taplick J, Geva N and Oren M: Inhibition of p53 degradation by Mdm2 acetylation. FEBS Lett. 561:195–201. 2004. View Article : Google Scholar : PubMed/NCBI
38	Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M: PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 30:193–204. 2004. View Article : Google Scholar : PubMed/NCBI
39	Gan YH and Zhang S: PTEN/AKT pathway involved in histone deacetylases inhibitor induced cell growth inhibition and apoptosis of oral squamous cell carcinoma cells. Oral Oncol. 45:e150–e154. 2009. View Article : Google Scholar : PubMed/NCBI
40	Song MS, Salmena L and Pandolfi PP: The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 13:283–296. 2012. View Article : Google Scholar : PubMed/NCBI
41	van Echten-Deckert G, Zschoche A, Bär T, Schmidt RR, Raths A, Heinemann T and Sandhoff K: cis-4-Methylsphingosine decreases sphingolipid biosynthesis by specifically interfering with serine palmitoyltransferase activity in primary cultured neurons. J Biol Chem. 272:15825–15833. 1997. View Article : Google Scholar : PubMed/NCBI
42	Nemoto S, Nakamura M, Osawa Y, Kono S, Itoh Y, Okano Y, Murate T, Hara A, Ueda H, Nozawa Y and Banno Y: Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation. J Biol Chem. 284:10422–10432. 2009. View Article : Google Scholar : PubMed/NCBI