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Epigenetic inactivation of ADAMTS9 via promoter methylation in multiple myeloma

Ling Peng1, Zesong Yang, Cui Tan

  • 1Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China.

Molecular Medicine Reports
|January 30, 2013
PubMed

Insights

ADAMTS9 gene silencing by DNA methylation is prevalent in multiple myeloma (MM). Restoring ADAMTS9 expression suppressed MM cell growth, suggesting its potential as a tumor marker and therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • ADAMTS9 is a tumor suppressor gene often downregulated in cancers via promoter hypermethylation.
  • Multiple myeloma (MM) is a cancer of plasma cells with complex genetic alterations.
  • Understanding gene silencing mechanisms in MM is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the silencing mechanism of the ADAMTS9 gene in multiple myeloma (MM) cell lines.
  • To determine the role of DNA methylation in ADAMTS9 gene silencing in MM.
  • To evaluate the therapeutic potential of restoring ADAMTS9 expression in MM.

Main Methods:

  • Analysis of ADAMTS9 gene expression using RT-PCR in normal and MM samples.
  • Detection of ADAMTS9 promoter methylation using methylation-specific PCR.
  • Treatment of MM cells with DNA demethylating agents (5-aza-2'-deoxycytidine and trichostatin A).
  • Assessment of cell proliferation and colony formation after ectopic ADAMTS9 expression.

Main Results:

  • ADAMTS9 was highly expressed in normal samples and RPMI-8226 cells but silenced in KM3 cells and most MM patients.
  • Promoter methylation of ADAMTS9 was detected in KM3 cells and 66% of MM patients.
  • Demethylating agents restored ADAMTS9 expression in KM3 cells by suppressing promoter methylation.
  • Ectopic expression of ADAMTS9 significantly inhibited MM cell colony formation and proliferation.

Conclusions:

  • DNA methylation plays a critical role in ADAMTS9 gene silencing and the biological behavior of myeloma cells.
  • ADAMTS9 silencing by methylation may serve as a novel tumor marker for MM.
  • Demethylating agents show potential applicability in the treatment of MM.

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