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

Laura Rodón; Robert U. Svensson; Ezra Wiater; Matthew G.H. Chun; Wen Wei Tsai; Lillian J. Eichner; Reuben J. Shaw; Marc Montminy

doi:10.1126/sciadv.aaw6455

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

Laura Rodón, Robert U. Svensson, Ezra Wiater, Matthew G.H. Chun, Wen Wei Tsai, Lillian J. Eichner, Reuben J. Shaw, Marc Montminy^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	eaaw6455
Journal	Science Advances
Volume	5
Issue number	7
DOIs	https://doi.org/10.1126/sciadv.aaw6455
State	Published - Jul 24 2019

Funding

We are grateful to T. Sonntag for technical help during the revision of the manuscript. We thank M. Green for the CRISPR-Cas9 CRTC2 construct, F. Ventura for the ID1 reporter construct, and N. S. Grey for the YKL-05-096 SIK inhibitor. This work was supported by grants to M.M. from the National Institutes of Health (R01 DK083834), The Leona M. and Harry B. Helmsley Charitable Trust, the Clayton Foundation for Medical Research, and the J. W. Kieckhefer Foundation. This study was supported by grants to R.J.S. from the National Institutes of Health (R35CA220538 and P01CA120964) and by The Leona M. and Harry B. Helmsley Charitable Trust grant no. 2012-PG-MED002. L.R. was supported by a postdoctoral fellowship from the Tobacco-Related Disease Research Program (25FT-0006). R.U.S. was supported by a postdoctoral fellowship from the American Cancer Society (ACS no. 124183-PF-13-023-01- CSM). L.J.E. was supported by a postdoctoral fellowship from the American Cancer Society (PF-15-037-01-DMC). The Salk CCSG P30 CA014195 and The Leona M. and Harry B. Helmsley Charitable Trust supported the Functional Genomics Core and the Bioinformatics Core and provide partial support for K. McIntyre and the histology core of the Salk Institute.

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title = "The CREB coactivator CRTC2 promotes oncogenesis in LKB1-mutant non–small cell lung cancer",

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.",

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AU - Shaw, Reuben J.

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

Abstract

Funding

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UN SDGs

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