title: Switch to full-length of XAF1 mRNA expression in prostate cancer cells by the DNA methylation inhibitor.
abstract: X-linked inhibitor of apoptosis protein (XIAP) suppresses apoptotic cell death by binding to caspases and inhibiting their functions, while the XIAP-associated factor1 (XAF1), a zinc finger protein, antagonizes XIAP activities, thereby promoting apoptosis. The aberrant silence of the XAF1 gene has recently been found in various types of cancer cells, which is suggested to be one of the potential mechanisms underlying survival advantages of malignant cells. In the present study, we investigated the XAF1 expression in prostate cancer cells. Compared with normal tissues where a full-length of XAF1 mRNA is predominant, LNCaP and DU145 prostate cancer cell lines only expressed a short form of XAF1 transcripts, whereas PC3 cells exhibited a complete silence of the XAF1 gene. Inhibition of DNA methylation led to a switch to the full length of XAF1 mRNA expression in LNCaP and DU145 cells. The down-regulation of XAF1 expression was also observed in 6/8 tumor samples derived from patients with prostate cancer. Our findings suggest that splicing alterations or downregulation of the XAF1 transcript may occur during the development of prostate cancers due to the aberrant DNA methylation. The alternative splicing of XAF1 mRNA leads to formation of a truncated XAF1 protein with 19 amino acid deletion in its zinc finger domain, which likely affects its functional interaction with XIAP, and consequently, contributes to the pathogenesis of prostate cancers by disrupting balance of the apoptosis machinery.
authors.affiliation: Department of Surgery, Division of Urology, Karolinska Hospital, and Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. xiaolei.fang@kirurgi.ki.se
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Fang
authors.forename: Zhaoxu
authors.initials: Z
authors.lastname: Liu
authors.forename: Yidong
authors.initials: Y
authors.lastname: Fan
authors.forename: Chengyun
authors.initials: C
authors.lastname: Zheng
authors.forename: Sten
authors.initials: S
authors.lastname: Nilson
authors.forename: Lars
authors.initials: L
authors.lastname: Egevad
authors.forename: Peter
authors.initials: P
authors.lastname: Ekman
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D019175:DNA Methylation; D015536:Down-Regulation; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C417551:XAF1 protein, human