title: Histone deacetylase 2 regulates doxorubicin (Dox) sensitivity of colorectal cancer cells by targeting ABCB1 transcription.
abstract: OBJECTIVE
  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.
authors: Department of Colorectal Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, 312000, China.
authors: Pingjiang
authors: P
authors: Ye
authors: Department of Intensive Care, Xiasha Campus, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, School of Medicine, Hangzhou, 310019, China.
authors: Haibo
authors: H
authors: Xing
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, School of Medicine, 3# Qingchun Eastern Road, Hangzhou, 310018, China.
authors: Fang
authors: F
authors: Lou
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, School of Medicine, 3# Qingchun Eastern Road, Hangzhou, 310018, China.
authors: Kaifeng
authors: K
authors: Wang
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, School of Medicine, 3# Qingchun Eastern Road, Hangzhou, 310018, China.
authors: Qin
authors: Q
authors: Pan
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, School of Medicine, 3# Qingchun Eastern Road, Hangzhou, 310018, China.
authors: Xiaoyun
authors: X
authors: Zhou
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, School of Medicine, 3# Qingchun Eastern Road, Hangzhou, 310018, China.
authors: Liu
authors: L
authors: Gong
authors: Department of Medical Oncology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, School of Medicine, 3# Qingchun Eastern Road, Hangzhou, 310018, China. lidazju@163.com.
authors: Da
authors: D
authors: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D003106:Colon / Q000166:cytology / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D045325:HCT116 Cells; D056464:Histone Deacetylase 2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D000089762:Multidrug Resistance-Associated Protein 2; D034741:RNA, Small Interfering; D004317:Doxorubicin; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: ABCB1; AP-1; CRC; Doxorubicin; HDAC2