Pharmacological methyl group donors block skeletal metastasis in vitro and in vivo

Br J Pharmacol. 2015 Jun;172(11):2769-81. doi: 10.1111/bph.13102. Epub 2015 Mar 27.


Background and purpose: DNA hypomethylation was previously implicated in metastasis. In the present study, we examined whether methyl supplementation with the universal methyl donor S-adenosylmethionine (SAM) inhibits prostate cancer associated skeletal metastasis.

Experimental approach: Highly invasive human prostate cancer cells PC-3 and DU-145 were treated with vehicle alone, S-adenosylhomocysteine (SAH) or SAM and their effects on tumour cell proliferation, invasion, migration and colony formation were monitored. For in vivo studies, control (SAH) and SAM-treated PC-3 cells were injected into the tibia of Fox chase SCID mice and skeletal lesions were determined by X-ray and μCT. To understand possible mechanisms involved, we delineated the effect of SAM on the genome-wide methylation profile of PC-3 cells.

Key results: Treatment with SAM resulted in a dose-dependent inhibition of tumour cell proliferation, invasion, cell migration, colony formation and cell cycle characteristics. Animals injected with 250 μM SAM-treated cells developed significantly smaller skeletal lesions, which were associated with increases in bone volume to tumour volume ratio and connectivity density as well as decreased trabecular spacing. Genome-wide methylation analysis showed differential methylation in several key signalling pathways implicated in prostate cancer including the signal transducer and activator of transcription 3 (STAT3) pathway. A selective STAT3 inhibitor decreased tumour cell invasion, effects which were less pronounced as compared with SAM.

Conclusions and implications: These studies provide a possible mechanism for the role of DNA demethylation in the development of skeletal metastasis and a rationale for the use of hypermethylation pharmacological agents to impede the development and progression of skeletal metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / secondary
  • Animals
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / secondary
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • DNA Methylation / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness / genetics
  • Neoplasm Metastasis / genetics
  • Neoplasm Transplantation
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • S-Adenosylmethionine / pharmacology*
  • Tibia / diagnostic imaging
  • Tibia / drug effects
  • X-Ray Microtomography


  • S-Adenosylmethionine