The CREB coactivator CRTC2 promotes oncogenesis in LKB1-mutant non-small cell lung cancer

Sci Adv. 2019 Jul 24;5(7):eaaw6455. doi: 10.1126/sciadv.aaw6455. eCollection 2019 Jul.

Abstract

The LKB1 tumor suppressor is often mutationally inactivated in non-small cell lung cancer (NSCLC). LKB1 phosphorylates and activates members of the AMPK family of Ser/Thr kinases. Within this family, the salt-inducible kinases (SIKs) modulate gene expression in part via the inhibitory phosphorylation of the CRTCs, coactivators for CREB (cAMP response element-binding protein). The loss of LKB1 causes SIK inactivation and the induction of the CRTCs, leading to the up-regulation of CREB target genes. We identified CRTC2 as a critical factor in LKB1-deficient NSCLC. CRTC2 is unphosphorylated and therefore constitutively activated in LKB1-mutant NSCLC, where it promotes tumor growth, in part via the induction of the inhibitor of DNA binding 1 (ID1), a bona fide CREB target gene. As ID1 expression is up-regulated and confers poor prognosis in LKB1-deficient NSCLC, our results suggest that small molecules that inhibit CRTC2 and ID1 activity may provide therapeutic benefit to individuals with NSCLC.

Publication types

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

MeSH terms

  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Carcinogenesis / metabolism*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Inhibitor of Differentiation Protein 1 / metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mice, SCID
  • Mutation / genetics*
  • Prognosis
  • Protein-Serine-Threonine Kinases / genetics*
  • Signal Transduction
  • Transcription Factors / metabolism*

Substances

  • CRTC2 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • ID1 protein, human
  • Inhibitor of Differentiation Protein 1
  • Transcription Factors
  • STK11 protein, human
  • Protein-Serine-Threonine Kinases