Epigenetic identification of ADAMTS18 as a novel 16q23.1 tumor suppressor frequently silenced in esophageal, nasopharyngeal and multiple other carcinomas

Abstract

Tumor Suppressor genes (TSGs) often locate at chromosomal regions with frequent deletions in tumors. Loss of 16q23 occurs frequently in multiple tumors, indicating the presence of critical TSGs at this locus, such as the well-studied WWOX. Herein we found that ADAMTS18, located next to WWOX, was significantly downregulated in multiple carcinoma cell lines. No deletion of ADAMTS18 was detected with multiplex differential DNA-PCR or high resolution 1-Mb array-based CGH analysis. Instead, methylation of the ADAMTS18 promoter CpG Island was frequently detected with methylation-specific PCR and bisulfite genome sequencing in multiple carcinoma cell lines and primary carcinomas, but not in any non-tumor cell line and normal epithelial tissue. Both pharmacological and genetic demethylation dramatically induced ADAMTS18 expression, indicating that CpG methylation directly contributes to the tumor-specific silencing of ADAMTS18. Ectopic ADAMTS18 expression leads to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells lacking the expression. Thus, through functional epigenetics, we identified ADAMTS18 as a novel functional tumor suppressor, being frequently inactivated epigenetically in multiple carcinomas.

The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

“…However, this concept is challenged by recent findings of several members showing to possess tumor suppressive functions (2)(3)(4)(5)(6). A disintegrins and metalloproteinases with thrombospondin motifs (ADAMTS), a family of extracellular metalloproteases, is structurally and functionally similar to matrix metalloproteinases (MMP) and ADAMs (7).…”

“…Clonogenicity was determined by measuring colonies growing in monolayer culture as described previously (6,21). HONE1 and KYSE150 cells (1 Â 10 5 per well) were seeded in a 12-well plate and were transiently transfected with pcDNA3.1(þ)-ADAMTS8-Flag plasmid or the pcDNA3.1 vector alone, using FuGENE 6 (Roche).…”

“…Dysregulated expression of ADAMTSs, such as ADAMTS1 (2), ADAMTS8, ADAMTS9 (5), ADAMTS12 (3), ADAMTS15 (4), ADAMTS18 (6), and ADAMTS20 (9,10), have been detected in diverse types of malignancies including lung, brain, breast, gastric, prostate, pancreatic cancers, and glioblastoma (8). Various ADAMTSs have been shown to regulate cell proliferation, adhesion, migration, angiogenesis, and intracellular signaling (8,11), thus involved in multiple tumor pathogenesis (1,6).…”

Chromosome 16q genes CDH1, CDH13 and ADAMTS18 are correlated and frequently methylated in human lymphoma

“…Porter et al (14) demonstrated that there was a downregulation of several members of the ADAMTS family, including ADAMTS18, in human breast cancer compared with non-neoplastic mammary tissues. In addition, silencing of ADAMTS18 by methylation of promoter CpG islands has been reported in multiple carcinoma cell lines, particularly in cell lines derived from esophageal and nasopharyngeal carcinomas (15).…”

DLEC1 is a functional 3p22.3 tumour suppressor silenced by promoter CpG methylation in colon and gastric cancers

“…Also, it is now well established that alternative epigenetic silencing, such as methylation of promoter CpG islands (CGIs), leads to the inactivation of TSGs in virtually all tumour types and plays significant roles in tumour initiation and progression (Jones and Baylin, 2002). In CRC, epigenetic silencing of multiple TSGs has been reported frequently, including MLH1, p16 INK4A , MGMT, VHL, APC, RASSF1A, HIC1, CHFR, ADAMTS18 and PCDH10 in various percentages of CRC tumours (Herman et al, 1998;Esteller et al, 2001;Kim et al, 2005;Ying et al, 2006;Jin et al, 2007 ). A growing list of TSGs with CGI methylation-mediated silencing has also been reported in gastric cancer (Leung et al, 2001).…”