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

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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.

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Acknowledgments

This research was supported by the Zhejiang Provincial Medical and Health Science and Technology Plan (No. 2015KYB217).

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Authors and Affiliations

  1. Department of Colorectal Surgery, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, 312000, China

    Pingjiang Ye

  2. Department of Intensive Care, Xiasha Campus, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, School of Medicine, Hangzhou, 310019, China

    Haibo Xing

  3. Department of Medical Oncology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, School of Medicine, 3# Qingchun Eastern Road, Hangzhou, 310018, China

    Fang Lou, Kaifeng Wang, Qin Pan, Xiaoyun Zhou, Liu Gong & Da Li

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Correspondence to Da Li.

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Ye, P., Xing, H., Lou, F. et al. Histone deacetylase 2 regulates doxorubicin (Dox) sensitivity of colorectal cancer cells by targeting ABCB1 transcription. Cancer Chemother Pharmacol 77, 613–621 (2016). https://doi.org/10.1007/s00280-016-2979-9

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