Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation.
Elife, 2021/06/18;10
Zhou X[1, 2], Li JW[3], Chen Z[1, 2], Ni W[1, 2, 4], Li X[1, 2], Yang R[1, 2], Shen H[1, 5], Liu J[6, 7], DeMayo FJ[7], Lu J[2, 3, 4], Kaye FJ[2, 8], Wu L[1, 2, 4]
Affiliations
PMID: 34142658
Impact factor: 8.713
Abstract
Lung cancer with loss-of-function of the LKB1 tumor suppressor is a common aggressive subgroup with no effective therapies. LKB1-deficiency induces constitutive activation of cAMP/CREB-mediated transcription by a family of three CREB-regulated transcription coactivators (CRTC1-3). However, the significance and mechanism of CRTC activation in promoting the aggressive phenotype of LKB1-null cancer remain poorly characterized. Here, we observed overlapping CRTC expression patterns and mild growth phenotypes of individual CRTC-knockouts in lung cancer, suggesting functional redundancy of CRTC1-3. We consequently designed a dominant-negative mutant (dnCRTC) to block all three CRTCs to bind and co-activate CREB. Expression of dnCRTC efficiently inhibited the aberrantly activated cAMP/CREB-mediated oncogenic transcriptional program induced by LKB1-deficiency, and specifically blocked the growth of human and murine LKB1-inactivated lung cancer. Collectively, this study provides direct proof for an essential role of the CRTC-CREB activation in promoting the malignant phenotypes of LKB1-null lung cancer and proposes the CRTC-CREB interaction interface as a novel therapeutic target.
Keywords: CRTC coactivators; LKB1; cancer biology; human; mouse; non-small cell lung cance; therapeutic target
MeSH terms
A549 Cells; AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; CRISPR-Cas Systems; Cell Line, Tumor; Cyclic AMP Response Element-Binding Protein; Gene Editing; Heterografts; Humans; Lung Neoplasms; Mice; Protein Serine-Threonine Kinases; Transcription Factors; Transcriptome
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