title: The metalloprotease ADAMTS8 displays antitumor properties through antagonizing EGFR-MEK-ERK signaling and is silenced in carcinomas by CpG methylation.
abstract: A disintegrins and metalloproteinases with thrombospondin motifs (ADAMTS) family members have been reported dysregulated in various cancers. Through refining a loss of heterozygosity locus at 11q25 by array-CGH, we identified ADAMTS8 as a novel candidate tumor suppressor gene. Although ADAMTS8 downregulation has been reported in several tumors, its biologic function and underlying mechanism remain largely unknown. Here, we found that ADAMTS8 is broadly expressed in normal tissues but frequently downregulated or silenced by promoter methylation in common carcinoma cell lines, including nasopharyngeal, esophageal squamous cell, gastric, and colorectal carcinomas. Pharmacologic or genetic demethylation restored ADAMTS8 expression, indicating that promoter methylation mediates its silencing. Aberrant methylation of ADAMTS8 was also detected in several types of primary tumors but rarely in normal tissues. Further functional studies showed that restoring ADAMTS8 expression suppressed tumor cell clonogenicity through inducing apoptosis. ADAMTS8 as a secreted protease inhibited epidermal growth factor receptor (EGFR) signaling along with decreased levels of phosphorylated MEK and ERK. We further found that ADAMTS8 disrupted actin stress fiber organization and inhibited tumor cell motility. Thus, our data demonstrate that ADAMTS8 metalloprotease acts as a functional tumor suppressor through antagonizing EGFR-MEK-ERK signaling, in addition to its previously reported anti-angiogenesis function, and is frequently methylated in common tumors.
  
  
  CONCLUSIONS
  This study uncovers the tumor suppressive function of ADAMTS8, one of the ADAMTS family members, and its frequent methylation in certain tumors could be developed as a potential biomarker.
authors.affiliation: Room 315, Cancer Center, PWH, The Chinese University of Hong Kong, Shatin, Hong Kong. qtao@clo.cuhk.edu.hk.
authors.forename: Gigi C G
authors.initials: GC
authors.lastname: Choi
authors.forename: Jisheng
authors.initials: J
authors.lastname: Li
authors.forename: Yajun
authors.initials: Y
authors.lastname: Wang
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Lan
authors.initials: L
authors.lastname: Zhong
authors.forename: Brigette
authors.initials: B
authors.lastname: Ma
authors.forename: Xianwei
authors.initials: X
authors.lastname: Su
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
authors.forename: Tingxiu
authors.initials: T
authors.lastname: Xiang
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Chan
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism*; D000071096:ADAMTS Proteins; D017209:Apoptosis; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002880:Chromosomes, Human, Pair 11; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C120807:ADAMTS8 protein, human