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SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway

Chor-Sang Chim1, Tsz-Kin Fung, Wai-Chung Cheung

  • 1University Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong.

Blood
|February 21, 2004
PubMed

Insights

Promoter hypermethylation epigenetically inactivates SHP1 in most myeloma patients, potentially activating the Jak/STAT pathway. Demethylation therapy restored SHP1, down-regulating STAT3 phosphorylation.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Biology

Background:

  • Suppressor of Cytokine Signaling 1 (SOCS1) and SH2 domain-containing phosphatase 1 (SHP1) are negative regulators of the Janus kinase/Signal Transducer and Activator of Transcription (Jak/STAT) pathway.
  • Epigenetic silencing via promoter hypermethylation is a known mechanism for gene inactivation in various cancers, including multiple myeloma.

Purpose of the Study:

  • To investigate the role of promoter hypermethylation in the epigenetic inactivation of SOCS1 and SHP1 in multiple myeloma.
  • To explore the biological significance of SHP1 methylation and its impact on the Jak/STAT pathway in myeloma.

Main Methods:

  • Methylation-specific polymerase chain reaction (MSP) was employed to assess SOCS1 and SHP1 promoter methylation in 34 diagnostic myeloma samples.
  • The U266 human myeloma cell line was used to study the effects of SHP1 methylation and 5-azacytidine treatment on SHP1 expression and STAT3 phosphorylation.
  • Reverse transcription-polymerase chain reaction (RT-PCR) was utilized to confirm SHP1 re-expression upon demethylation.

Main Results:

  • No significant SOCS1 promoter methylation was detected in myeloma samples using specific promoter region primers.
  • SHP1 hypermethylation was observed in 79.4% (27 of 34) of myeloma samples.
  • In the U266 cell line, SHP1 demethylation induced by 5-azacytidine led to progressive SHP1 re-expression and a parallel down-regulation of phosphorylated STAT3.

Conclusions:

  • SHP1 promoter hypermethylation is a frequent event in multiple myeloma, suggesting epigenetic inactivation of this tumor suppressor.
  • Epigenetic inactivation of SHP1 may contribute to the activation of the Jak/STAT pathway in myeloma pathogenesis.
  • Further functional studies are warranted to confirm the role of SHP1 methylation in myeloma development and progression.

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