Nutrient availability shapes methionine metabolism in p16/MTAP-deleted cells.

Journal Article (Journal Article)

Codeletions of gene loci containing tumor suppressors and neighboring metabolic enzymes present an attractive synthetic dependency in cancers. However, the impact that these genetic events have on metabolic processes, which are also dependent on nutrient availability and other environmental factors, is unknown. As a proof of concept, we considered panels of cancer cells with homozygous codeletions in CDKN2a and MTAP, genes respectively encoding the commonly-deleted tumor suppressor p16 and an enzyme involved in methionine metabolism. A comparative metabolomics analysis revealed that while a metabolic signature of MTAP deletion is apparent, it is not preserved upon restriction of nutrients related to methionine metabolism. Furthermore, re-expression of MTAP exerts heterogeneous consequences on metabolism across isogenic cell pairs. Together, this study demonstrates that numerous factors, particularly nutrition, can overwhelm the effects of metabolic gene deletions on metabolism. These findings may also have relevance to drug development efforts aiming to target methionine metabolism.

Full Text

Duke Authors

Cited Authors

  • Sanderson, SM; Mikhael, PG; Ramesh, V; Dai, Z; Locasale, JW

Published Date

  • June 2019

Published In

Volume / Issue

  • 5 / 6

Start / End Page

  • eaav7769 -

PubMed ID

  • 31249865

Pubmed Central ID

  • PMC6594760

Electronic International Standard Serial Number (EISSN)

  • 2375-2548

Digital Object Identifier (DOI)

  • 10.1126/sciadv.aav7769


  • eng

Conference Location

  • United States