MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis

Cell Rep. 2016 Apr 19;15(3):574-587. doi: 10.1016/j.celrep.2016.03.043. Epub 2016 Apr 7.

Abstract

Homozygous deletions of p16/CDKN2A are prevalent in cancer, and these mutations commonly involve co-deletion of adjacent genes, including methylthioadenosine phosphorylase (MTAP). Here, we used shRNA screening and identified the metabolic enzyme, methionine adenosyltransferase II alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. The MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss. Biochemical profiling of a methyltransferase enzyme panel revealed that MTA is a potent and selective inhibitor of PRMT5. MTAP-deleted cells have reduced PRMT5 methylation activity and increased sensitivity to PRMT5 depletion. MAT2A produces the PRMT5 substrate S-adenosylmethionine (SAM), and MAT2A depletion reduces growth and PRMT5 methylation activity selectively in MTAP-deleted cells. Furthermore, this vulnerability extends to PRMT5 co-complex proteins such as RIOK1. Thus, the unique biochemical features of PRMT5 create an axis of targets vulnerable in CDKN2A/MTAP-deleted cancers.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Antigens, Neoplasm / metabolism*
  • Gene Deletion*
  • Genomics
  • HCT116 Cells
  • Humans
  • Methionine Adenosyltransferase / metabolism*
  • Multiprotein Complexes / metabolism
  • Neoplasms / enzymology*
  • Neoplasms / metabolism
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Purine-Nucleoside Phosphorylase / deficiency
  • Purine-Nucleoside Phosphorylase / metabolism*
  • RNA, Small Interfering / metabolism
  • Signal Transduction*
  • Thionucleosides / metabolism*

Substances

  • AD034 antigen, human
  • Antigens, Neoplasm
  • Multiprotein Complexes
  • RNA, Small Interfering
  • Thionucleosides
  • 2-methylthioadenosine
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases
  • Purine-Nucleoside Phosphorylase
  • 5'-methylthioadenosine phosphorylase
  • MAT2A protein, human
  • Methionine Adenosyltransferase
  • Protein-Serine-Threonine Kinases
  • Adenosine