title: Arsenic trioxide suppresses transcription of hTERT through down-regulation of multiple transcription factors in HL-60 leukemia cells.
abstract: Acute promyelocytic leukemia (APL) is largely caused by the t(15,17) chromosome translocation, leading to the production of the PML/retinoic acid receptor alpha fusion. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), as a monotherapy or combination therapy, have been successfully used to treat APL primarily by targeting the degradation of the fusion protein. We previously observed that ATO treatment induced cell death in APL cell line HL-60 accompanied by inhibition of the human telomere reverse transcriptase (hTERT) activity, a critical enzyme responsible for the control of cell replication and transformation in cancer cells. In the present study, we investigated the underlying mechanism by which hTERT activity is inhibited by ATO in HL-60 cells. Our results showed that ATO down-regulated the expression of hTERT at both mRNA and protein levels. Further molecular analysis revealed that the expression of four transcription factors Sp1, c-Myc, NF-κB and USF2, which are located in the proximate promoter region (-1126 to -47) of hTERT, was also suppressed by ATO. Notably, we observed that down-regulation of these four factors by their siRNAs potentiates ATO-induced cell growth inhibition and apoptosis. Therefore, our results provide a novel mechanism of action of ATO for the treatment of APL.
authors.affiliation: Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Donghu Road 169, Wuhan 430071, China; Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu 241000, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Clinical Laboratories of Bengbu Medical College, Anhui 233030, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.affiliation: Clinical Laboratories of Bengbu Medical College, Anhui 233030, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Clinical Laboratories of Bengbu Medical College, Anhui 233030, China.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Clinical Laboratories of Bengbu Medical College, Anhui 233030, China.
authors.forename: Changjie
authors.initials: C
authors.lastname: Chen
authors.affiliation: The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, China. Electronic address: zhiweichina@126.com.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Donghu Road 169, Wuhan 430071, China. Electronic address: zhouxjyk@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D010087:Oxides / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
chemical_list: D001152:Arsenicals; D010087:Oxides; D034741:RNA, Small Interfering; D014157:Transcription Factors; D008156:Luciferases; C509186:TERT protein, human; D019098:Telomerase; D000077237:Arsenic Trioxide
keywords: APL; Arsenic trioxide; HL-60; Promoter; Transcription; hTERT