Lung cancer is the most common cause of cancer death for women and men. Given this, there is a pressing need to improve lung cancer prevention and treatment. This is the subject of this competing renewal of NIH R01-CA087546-10 that takes advantage of a previously unrecognized chemoprevention pathway uncovered during the prior funding period. This is constituted by the E1- like ubiquitin-activating enzyme (UBE1L), which partners with the ubiquitin-related interferon stimulated gene 15 (ISG15) that can destabilize cyclin D1 and other complexed proteins. The consequence is G1 checkpoint arrest that permits repair of carcinogenic DNA damage. Notably, the specific UBE1L-ISG15 deconjugase UBP43/USP18 is a key regulator of this pathway. We propose this as target for chemoprevention and hypothesize that targeting UPB43 destabilizes cyclin D1 and other ISG15 complexed proteins. This confers therapeutic and chemopreventive effects in the lung. This hypothesis will be pursued through these Specific Aims: (1) to learn whether UBP43 is a key regulator of the G1-S transition;(2) to establish whether UBP43 knock-down represses lung cancer growth, tumorigenicity, or affects response to chemotherapy and chemoprevention agents;and (3) to validate the biological and clinical relevance of this pathway using novel transgenic mouse models that we engineered to mimic key features of clinical lung cancer. We will cross these mice with those that have lung-specific loss of UBP43 and interrogate a paired normal-malignant lung tissue bank and a lung cancer tissue array that permits clinical associations. Intriguingly, our proof of principle trial platform at Dartmouth found this pathway is engaged in lung cancers of patients treated with the rexinoid bexarotene, a candidate chemopreventive agent. Unique cellular, biochemical, experimental and clinically-predictive transgenic mouse models as well as paired normal-malignant lung tissue banks will be used by our highly collaborative and interdisciplinary team. Successful completion of this proposal should have substantial translational impact. This would uncover a novel pharmacologic target to combat lung cancer, a major cancer problem that we must confront.

Public Health Relevance

Lung cancer is the most common cause of cancer death for both men and women. Given this, there is a pressing need to find better ways to treat and prevent lung cancer. This is the subject of this NIH R0-1 competing renewal application that seeks to investigate whether the deconjugase UBP43 is a target for lung cancer prevention or therapy by conferring anti-neoplastic effects via induced degradation of cyclin D1.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dartmouth College
Schools of Medicine
United States
Zip Code
Mustachio, Lisa Maria; Lu, Yun; Kawakami, Masanori et al. (2018) Evidence for the ISG15-Specific Deubiquitinase USP18 as an Antineoplastic Target. Cancer Res 78:587-592
Chen, Limo; Diao, Lixia; Yang, Yongbin et al. (2018) CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade. Cancer Discov 8:1156-1175
Kawakami, Masanori; Mustachio, Lisa Maria; Liu, Xi et al. (2018) Engaging Anaphase Catastrophe Mechanisms to Eradicate Aneuploid Cancers. Mol Cancer Ther 17:724-731
Kawakami, Masanori; Mustachio, Lisa Maria; Zheng, Lin et al. (2018) Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers. Proc Natl Acad Sci U S A 115:1913-1918
Sepesi, Boris; Gold, Kathryn A; Correa, Arlene M et al. (2017) The Influence of Body Mass Index on Overall Survival Following Surgical Resection of Non-Small Cell Lung Cancer. J Thorac Oncol 12:1280-1287
Kawakami, Masanori; Mustachio, Lisa Maria; Rodriguez-Canales, Jaime et al. (2017) Next-Generation CDK2/9 Inhibitors and Anaphase Catastrophe in Lung Cancer. J Natl Cancer Inst 109:
Mustachio, Lisa Maria; Lu, Yun; Tafe, Laura J et al. (2017) Deubiquitinase USP18 Loss Mislocalizes and Destabilizes KRAS in Lung Cancer. Mol Cancer Res 15:905-914
Mustachio, Lisa Maria; Kawakami, Masanori; Lu, Yun et al. (2017) The ISG15-specific protease USP18 regulates stability of PTEN. Oncotarget 8:3-14
Yim, Christina Y; Sekula, David J; Hever-Jardine, Mary P et al. (2016) G0S2 Suppresses Oncogenic Transformation by Repressing a MYC-Regulated Transcriptional Program. Cancer Res 76:1204-13
Danilov, Alexey V; Hu, Shanhu; Orr, Bernardo et al. (2016) Dinaciclib Induces Anaphase Catastrophe in Lung Cancer Cells via Inhibition of Cyclin-Dependent Kinases 1 and 2. Mol Cancer Ther 15:2758-2766

Showing the most recent 10 out of 74 publications