title: High-expressing cystic fibrosis transmembrane conductance regulator interacts with histone deacetylase 2 to promote the development of Ph+ leukemia through the HDAC2-mediated PTEN pathway.
abstract: The aberrant expression or mutation of CFTR has been shown to be involved in several tumors, but how mutations or dysfunction of CFTR may increase the risk of malignancies in various tissues remains unclear. Here, we report the interaction between CFTR and HDAC2, and its involvement in the development of Ph+ leukemia. We first detected the physical interaction and co-localization of CFTR and HDAC2 in Ph+ leukemia cell lines. And treatment with CFTRinh-172, a CFTR inhibitor, reduced the expression of HDAC2 protein in K562 and SUP-B15 cells, which could be partially recovered by MG132, a proteasome inhibitor. Additionally, high expression levels of HDAC2 protein were observed in CFTR cDNA transfected HEK-293 and Ba/F3 cells. Next, we found that HDAC2 bound in the promoter region of the PTEN gene, and treatment with HDAC2 inhibitor or CFTRinh-172 resulted in an increase in PTEN mRNA and protein levels and a decrease in PDK1 and mTOR (downstream signaling of PTEN) activity. Finally, the MTT assay revealed that CFTRinh-172 could strengthen the anti-proliferation effect of HDAC2 inhibitor on Ph+ leukemia cells. Altogether, this study provides strong evidence that high-expression CFTR plays an important role in the development of Ph+ leukemia through the HDAC2-mediated PTEN pathway.
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China.
authors.forename: Tianyou
authors.initials: T
authors.lastname: Yan
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Leng
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China. Electronic address: gongyuping2010@aliyun.com.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Gong
authors.affiliation: SCU-CUHK Joint Laboratory for Reproductive Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Department of Pediatrics, West China Second University Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China.
authors.forename: Huaqin
authors.initials: H
authors.lastname: Sun
authors.affiliation: SCU-CUHK Joint Laboratory for Reproductive Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Department of Pediatrics, West China Second University Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: SCU-CUHK Joint Laboratory for Reproductive Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Department of Pediatrics, West China Second University Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China.
authors.forename: Wenming
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China.
authors.forename: Duolan
authors.initials: D
authors.lastname: Naren
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 37 GuoXue Xiang, Chengdu, Sichuan Province 610041, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Shi
mesh_terms: D045744:Cell Line, Tumor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D057809:HEK293 Cells; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014162:Transfection
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2
keywords: CFTRinh-172; Cystic fibrosis transmembrane conductance regulator (CFTR); Histone deacetylase (HDAC); Leukemia; Philadelphia chromatin; Phosphatase and tensin homolog (PTEN)