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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 3/2016

01-03-2016 | Original Article

Histone deacetylase 2 regulates doxorubicin (Dox) sensitivity of colorectal cancer cells by targeting ABCB1 transcription

Authors: Pingjiang Ye, Haibo Xing, Fang Lou, Kaifeng Wang, Qin Pan, Xiaoyun Zhou, Liu Gong, Da Li

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2016

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Abstract

Purpose

Histone deacetylases (HDACs) have been shown to regulate cell cycle, differentiation, and apoptosis of colorectal cancer (CRC) cells, while their roles in drug sensitivity remain unclear. The objectives of the present study were to investigate the effects of HDAC2 on drug resistance of CRC cells.

Methods

We measured the expression of class I HDACs (HDAC1, 2, 3, 8) in CRC and human normal colonic epithelial cells. Additionally, we inhibited HDAC2 via siRNA or overexpressed it via pcDNA/HDAC2 transfection to evaluate its roles in doxorubicin (Dox) sensitivity.

Results

Our present study showed HDAC2 was significantly increased in CRC cell lines as compared to human normal colonic epithelial cells. Silencing of HDAC2 can obviously enhance the sensitivity of HCT-116 and SW480 cells to dDox. Further, knockdown of HDAC2 can significantly (p < 0.05) downregulate the expression of ABCB1, while not ABCG2, ABCC1, ABCA1, or ABCC2. Inhibition of HDAC2 decreased ABCB1 promoter activities and the phosphorylation of c-fos and c-Jun, which can directly interact with the ABCB1 promoter and then promote its transcription. Overexpression of HDAC2 by pcDNA/HDAC2 transfection significantly increased the sensitivity of CRC cells to Dox and upregulated the levels of P-gp, p-c-fos, and p-c-Jun.

Conclusions

Our data revealed that HDAC2 can regulate Dox sensitivity of CRC cells by targeting ABCB1 transcription. It suggested that HDAC2 might be an important target for CRC therapy. Further, the combination of HDAC2-specific inhibitor and anticancer drugs including Dox might be an efficiency approach to elevate the treatment outcome of CRC.
Literature
1.
Garborg K, Holme O, Loberg M, Kalager M, Adami HO, Bretthauer M (2013) Current status of screening for colorectal cancer. Ann Oncol 24:1963–1972CrossRefPubMed
2.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2012) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108CrossRef
3.
Schule S, Dittmar Y, Knosel T et al (2013) Long-term results and prognostic factors after resection of hepatic and pulmonary metastases of colorectal cancer. Int J Colorectal Dis 28:537–545CrossRefPubMed
4.
Nooter K, Stoter G (1996) Molecular mechanisms of multidrug resistance in cancer chemotherapy. Pathol Res Pract 192:768–780CrossRefPubMed
5.
6.
Zhu P, Martin E, Mengwasser J, Schlag P, Janssen KP, Gottlicher M (2004) Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5:455–463CrossRefPubMed
7.
8.
Kaler P, Sasazuki T, Shirasawa S, Augenlicht L, Klampfer L (2008) HDAC2 deficiency sensitizes colon cancer cells to TNF alpha-induced apoptosis through inhibition of NF-kappa B activity. Exp Cell Res 314:1507–1518CrossRefPubMed
9.
Ashktorab H, Belgrave K, Hosseinkhah F et al (2009) Global histone H4 Acetylation and HDAC2 expression in colon adenoma and carcinoma. Dig Dis Sci 54:2109–2117PubMedCentralCrossRefPubMed
10.
11.
Noh JH, Bae HJ, Eun JW et al (2014) HDAC2 provides a critical support to malignant progression of hepatocellular carcinoma through feedback control of mTORC1 and AKT. Cancer Res 74:1728–1738CrossRefPubMed
12.
Jung KH, Noh JH, Kim JK et al (2012) HDAC2 overexpression confers oncogenic potential to human lung cancer cells by deregulating expression of apoptosis and cell cycle proteins. J Cell Biochem 113:2167–2177CrossRefPubMed
13.
Colombo V, Lupi M, Falcetta F, Forestieri D, D’Incalci M, Ubezio P (2011) Chemotherapeutic activity of silymarin combined with doxorubicin or paclitaxel in sensitive and multidrug-resistant colon cancer cells. Cancer Chemother Pharmacol 67:369–379CrossRefPubMed
14.
Yang F, Teves SS, Kemp CJ, Henikoff S (2014) Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta 1845:84–89PubMedCentralPubMed
15.
Lee CC, Gillies ER, Fox ME et al (2006) A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas. Proc Natl Acad Sci 103:16649–16654PubMedCentralCrossRefPubMed
16.
Li M, Tang Z, Zhang D et al (2015) Doxorubicin-loaded polysaccharide nanoparticles suppress the growth of murine colorectal carcinoma and inhibit the metastasis of murine mammary carcinoma in rodent models. Biomaterials 51:161–172CrossRefPubMed
17.
Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58CrossRefPubMed
18.
Cowin PA, George J, Fereday S et al (2012) LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin. Cancer Res 72:4060–4073CrossRefPubMed
19.
Doublier S, Belisario DC, Polimeni M et al (2012) HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P-glycoprotein expression: a potential model of the chemoresistance of invasive micropapillary carcinoma of the breast. BMC Cancer 12:4. doi:10.​1186/​1471-2407-12-4 PubMedCentralCrossRefPubMed
20.
Meidhof S, Brabletz S, Lehmann W et al (2015) ZEB1-associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat. EMBO Mol Med 7:831–847PubMedCentralCrossRefPubMed
21.
Tsai YT, Lozanski G, Lehman A et al (2015) BRAF induces ABCB1/P-glycoprotein expression and drug resistance in B-cells via AP-1 activation. Leuk Res 15:30371–30374
22.
Sissung TM, Baum CE, Kirkland CT, Gao R, Gardner ER, Figg WD (2010) Pharmacogenetics of membrane transporters: an update on current approaches. Mol Biotechnol 44:152–167CrossRefPubMed
23.
Wang Y, Zhang D, Wu K, Zhao Q, Nie Y, Fan D (2014) Long noncoding RNA MRUL promotes ABCB1 expression in multidrug-resistant gastric cancer cell sublines. Mol Cell Biol 34:3182–3193PubMedCentralCrossRefPubMed
24.
Rodrigues AC, Curi R, Hirata MH, Hirata RD (2009) Decreased ABCB1 mRNA expression induced by atorvastatin results from enhanced mRNA degradation in HepG2 cells. Eur J Pharm Sci 37:486–491CrossRefPubMed
25.
Sundseth R, MacDonald G, Ting J, King AC (1997) DNA elements recognizing NF-Y and Sp1 regulate the human multidrug-resistance gene promoter. Mol Pharmacol 51:963–971PubMed
26.
Jepsen K, Rosenfeld MG (2002) Biological roles and mechanistic actions of co-repressor complexes. J Cell Sci 115:689–698PubMed
27.
Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6:38–51CrossRefPubMed
28.
Zimmermann S, Kiefer F, Prudenziati M et al (2007) Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice. Cancer Res 67:9047–9054CrossRefPubMed
29.
Fritsche P, Seidler B, Schuler S et al (2009) HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA. Gut 58:1399–1409CrossRefPubMed
30.
Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63:7291–7300PubMed
31.
Maiso P, Colado E, Ocio EM et al (2009) The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair. Leukemia 23:2265–2274CrossRefPubMed
32.
Catalano MG, Fortunati N, Pugliese M et al (2006) Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells. J Endocrinol 191:465–472CrossRefPubMed
33.
Pan L, Lu J, Wang X et al (2007) Histone deacetylase inhibitor trichostatin a potentiates doxorubicin-induced apoptosis by up-regulating PTEN expression. Cancer 109:1676–1688CrossRefPubMed
34.
Sims JT, Ganguly SS, Bennett H, Friend JW, Tepe J, Plattner R (2013) Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-kappaB and HSP27/p38/AKT pathways and by inhibiting ABCB1. PLoS One 8:e55509PubMedCentralCrossRefPubMed
35.
Lee WK, Chakraborty PK, Thevenod F (2013) Pituitary homeobox 2 (PITX2) protects renal cancer cell lines against doxorubicin toxicity by transcriptional activation of the multidrug transporter ABCB1. Int J Cancer 133:556–567CrossRefPubMed
36.
Hui RC, Francis RE, Guest SK et al (2008) Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells. Mol Cancer Ther 7:670–678CrossRefPubMed
37.
Kuo MT, Liu Z, Wei Y et al (2002) Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-kappaB signaling. Oncogene 21:1945–1954CrossRefPubMed
38.
Hatle KM, Neveu W, Dienz O et al (2007) Methylation-controlled J protein promotes c-Jun degradation to prevent ABCB1 transporter expression. Mol Cell Biol 27:2952–2966PubMedCentralCrossRefPubMed
39.
Hung TH, Chen CM, Tseng CP et al (2014) FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells. Int J Biochem Cell Biol 53:55–65CrossRefPubMed
40.
Hayakawa J, Depatie C, Ohmichi M, Mercola D (2003) The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair. J Biol Chem 278:20582–20592CrossRefPubMed
41.
Shi R, Peng H, Yuan X et al (2013) Down-regulation of c-fos by shRNA sensitizes adriamycin-resistant MCF-7/ADR cells to chemotherapeutic agents via P-glycoprotein inhibition and apoptosis augmentation. J Cell Biochem 114:1890–1900CrossRefPubMed
42.
Cripe LD, Gelfanov VM, Smith EA et al (2002) Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML): signaling to multidrug-efflux and hyperproliferation. Leukemia 16:799–812CrossRefPubMed
43.
Ledoux S, Yang R, Friedlander G, Laouari D (2003) Glucose depletion enhances P-glycoprotein expression in hepatoma cells: role of endoplasmic reticulum stress response. Cancer Res 63:7284–7290PubMed
44.
Sui H, Fan ZZ, Li Q (2012) Signal transduction pathways and transcriptional mechanisms of ABCB1/Pgp-mediated multiple drug resistance in human cancer cells. J Int Med Res 40:426–435CrossRefPubMed
Metadata
Title
Histone deacetylase 2 regulates doxorubicin (Dox) sensitivity of colorectal cancer cells by targeting ABCB1 transcription
Authors
Pingjiang Ye
Haibo Xing
Fang Lou
Kaifeng Wang
Qin Pan
Xiaoyun Zhou
Liu Gong
Da Li
Publication date
01-03-2016
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 3/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-016-2979-9

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