A novel TRPM7/O-GlcNAc axis mediates tumour cell motility and metastasis by stabilising c-Myc and caveolin-1 in lung carcinoma

Br J Cancer. 2020 Oct;123(8):1289-1301. doi: 10.1038/s41416-020-0991-7. Epub 2020 Jul 20.


Background: Calcium is an essential signal transduction element that has been associated with aggressive behaviours in several cancers. Cell motility is a prerequisite for metastasis, the major cause of lung cancer death, yet its association with calcium signalling and underlying regulatory axis remains an unexplored area.

Methods: Bioinformatics database analyses were employed to assess correlations between calcium influx channels and clinical outcomes in non-small cell lung cancer (NSCLC). Functional and regulatory roles of influx channels in cell migration and invasion were conducted and experimental lung metastasis was examined using in vivo live imaging.

Results: High expression of TRPM7 channel correlates well with the low survival rate of patients and high metastatic potential. Inhibition of TRPM7 suppresses cell motility in various NSCLC cell lines and patient-derived primary cells and attenuates experimental lung metastases. Mechanistically, TRPM7 acts upstream of O-GlcNAcylation, a post-translational modification and a crucial sensor for metabolic changes. We reveal for the first time that caveolin-1 and c-Myc are favourable molecular targets of TRPM7/O-GlcNAc that regulates NSCLC motility. O-GlcNAcylation of caveolin-1 and c-Myc promotes protein stability by interfering with their ubiquitination and proteasomal degradation.

Conclusions: TRPM7/O-GlcNAc axis represents a potential novel target for lung cancer therapy that may overcome metastasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / chemistry*
  • Animals
  • Calcium / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Caveolin 1 / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Humans
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • TRPM Cation Channels / antagonists & inhibitors
  • TRPM Cation Channels / physiology*


  • CAV1 protein, human
  • Caveolin 1
  • Proto-Oncogene Proteins c-myc
  • TRPM Cation Channels
  • Protein Serine-Threonine Kinases
  • TRPM7 protein, human
  • Calcium
  • Acetylglucosamine