NRF2 regulates serine biosynthesis in non-small cell lung cancer Academic Article uri icon

Overview

MeSH Major

  • Adenocarcinoma
  • Biomarkers, Tumor
  • Carcinoma, Non-Small-Cell Lung
  • Gene Expression Regulation, Neoplastic
  • Lung Neoplasms
  • NF-E2-Related Factor 2
  • Serine

abstract

  • Tumors have high energetic and anabolic needs for rapid cell growth and proliferation, and the serine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. We integrated metabolic tracing and transcriptional profiling of a large panel of non-small cell lung cancer (NSCLC) cell lines to characterize the activity and regulation of the serine/glycine biosynthetic pathway in NSCLC. Here we show that the activity of this pathway is highly heterogeneous and is regulated by NRF2, a transcription factor frequently deregulated in NSCLC. We found that NRF2 controls the expression of the key serine/glycine biosynthesis enzyme genes PHGDH, PSAT1 and SHMT2 via ATF4 to support glutathione and nucleotide production. Moreover, we show that expression of these genes confers poor prognosis in human NSCLC. Thus, a substantial fraction of human NSCLCs activates an NRF2-dependent transcriptional program that regulates serine and glycine metabolism and is linked to clinical aggressiveness.

publication date

  • December 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4721512

Digital Object Identifier (DOI)

  • 10.1038/ng.3421

PubMed ID

  • 26482881

Additional Document Info

start page

  • 1475

end page

  • 81

volume

  • 47

number

  • 12