Epigenetic inactivation of ADAMTS9 via promoter methylation in multiple             myeloma.
A disintegrin‑like and metalloprotease with thrombospondin type Ⅰ motifs (ADAMTS)             are a family of 19 secreted mammalian metalloproteases. ADAMTS9 was reported to             be a novel tumor suppressor gene and is downregulated in various types of human             cancer due to hypermethylation of promoter CpG islands. In the present study,             the silencing mechanism of the ADAMTS9 gene was analyzed in the multiple myeloma             (MM) cell lines, KM3 and RPMI‑8226. Control and MM samples were obtained by conventional             bone marrow (BM) biopsy of normal and MM adult BM, respectively. RT‑PCR revealed             a high expression of the ADAMTS9 gene in normal samples and RPMI‑8226 cells while             marked gene silencing of ADAMTS9 was observed in MM patients and KM3 cells. Promoter             methylation of ADAMTS9 was detected in the KM3 cell line and 66% (37/56) MM patients             by methylation‑specific PCR. In addition, the DNA demethylating agent, 5‑aza‑2'‑deoxycytidine             and trichostatin A restored ADAMTS9 expression by suppressing promoter methylation             in KM3 cells. Ectopic expression of ADAMTS9 in ADAMTS9‑silenced MM cells was found             to significantly suppress cell colony formation and proliferation. In the present             study, DNA methylation was found to play a key role in ADAMTS9 gene silencing             and the biological behavior of myeloma cells. The results demonstrate that ADAMTS9             silencing by methylation may be a novel tumor marker for MM and the applicability             of demethylating agents in the treatment of MM.
Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.
Ling
L
Peng
Zesong
Z
Yang
Cui
C
Tan
Guosheng
G
Ren
Jianbin
J
Chen
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071119:ADAMTS9 Protein; D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects
D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; C012589:trichostatin A; D000077209:Decitabine; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human; D001374:Azacitidine