Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation
Xin Zhou1,2, Jennifer W Li3, Zirong Chen1,2
1Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, United States.
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.
Insights
Loss of LKB1 in lung cancer activates CRTCs, driving tumor growth. Blocking CRTC-CREB interaction with dnCRTC inhibits aggressive LKB1-null lung cancer, offering a new therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Lung cancer with LKB1 loss-of-function is aggressive and lacks effective treatments.
- LKB1 deficiency leads to constitutive cAMP/CREB-mediated transcription via CRTC1-3 coactivators.
- The role of CRTC activation in LKB1-null lung cancer aggressiveness is unclear.
Purpose of the Study:
- To investigate the significance and mechanism of CRTC activation in LKB1-null lung cancer.
- To determine if CRTCs are essential for the aggressive phenotype of LKB1-inactivated lung cancer.
- To explore the CRTC-CREB interaction as a potential therapeutic target.
Main Methods:
- Analyzed CRTC expression patterns and knockout phenotypes in lung cancer models.
- Designed and utilized a dominant-negative mutant (dnCRTC) to inhibit CRTC1-3 function.
- Assessed the effect of dnCRTC on cAMP/CREB transcriptional activity and cancer cell growth.
Main Results:
- CRTC1-3 showed overlapping expression and functional redundancy in lung cancer.
- dnCRTC expression blocked aberrant cAMP/CREB transcription induced by LKB1 deficiency.
- dnCRTC specifically inhibited the growth of human and murine LKB1-inactivated lung cancer.
Conclusions:
- CRTC-CREB activation is essential for the malignant phenotype of LKB1-null lung cancer.
- The CRTC-CREB interaction represents a promising novel therapeutic target for this cancer subtype.
