Cigarette smoke and pro-inflammatory cytokines are directly linked to the initiation, progression, and metastasis of lung cancer. We have shown that primary cigarette smoke, nicotine, and the tobacco carcinogen NNK as well as the cytokine TNF suppress the metastasis suppressor gene BRMS1 which we have shown to inhibit metastasis in lung cancer. The purpose of this proposal is to characterize and better understand the regulation of BRMS1 at an epigenetic and post-translational level in lung cancer. Given that the majority of lung cancer patients present with metastatic disease and that it remains the number one cancer killer in the world, understanding how BRMS1 is regulated both transcriptionally and through post-translational modifications is important. Experiments described in Aim I of this proposal will investigate how the transcription factor NF-kB regulates methylation and transcriptional silencing of the BRMS1 promoter. Specifically, RelA/65, the transcriptionally active subunit of NF-kB, binds to BRMS1 DNA and promotes DNA and histone methyltransferases recruitment to chromatin which transcriptionally silences BRMS1. The goal of this aim is determine the mechanisms through which RelA/p65 regulates BRMS1 transcription and to extend these observations using human lung cancer specimens. In addition to transcriptional regulation of BRMS1, TNF, nicotine and NNK enhance casein kinase II mediated post-translational modifications of BRMS1 protein, including phosphorylation and ubiquitination which target BRMS1 to the proteasome. Experiments in Aim II of the proposal will identify specific casein kinase II phosphorylation residues in BRMS1 and what effect mutation(s) of these sites have on BRMS1 nuclear exportation and subsequent ubiquitination and proteasome- mediated degradation. Other experiments will map specific lysine residues that are ubiquitinated using mass spectroscopy and what effect mutations of these functionally relevant lysine residue(s) have on BRMS1 protein expression. Experiments proposed in Aim III use an inducible Cre/lox-P system lung cancer metastasis mouse model to explore the specific and separate contribution(s) of transcriptional and casein-kinase II mediated post- translational modifications of BRMS1 to the development of metastases. Collectively, experiments outlined in this proposal will elucidate the mechanisms through which BRMS1 is independently regulated at the chromatin level and through post-translational modifications. Our observations that BRMS1 is regulated by these two mechanisms and that its suppression can occur independent of selected inhibition of one mechanism has significant translational potential and speaks directly to the putative clinical cancer relevance and the significance of the project.

Public Health Relevance

Lung cancer is the number one cancer killer in the United States and most people present with advanced stage or metastatic disease. Our research is focused on understanding how a specific protein called BRMS1 helps regulate lung cancer metastases. The overall goal of this research is to improve our understanding of how lung cancer spreads, which ultimately is necessary in order to design novel targeted therapies for this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136705-02
Application #
7878759
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$314,363
Indirect Cost
Name
University of Virginia
Department
Surgery
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Brandt, Whitney S; Bouabdallah, Ilies; Tan, Kay See et al. (2018) Factors associated with distant recurrence following R0 lobectomy for pN0 lung adenocarcinoma. J Thorac Cardiovasc Surg 155:1212-1224.e3
Bucciarelli, Peter R; Tan, Kay See; Chudgar, Neel P et al. (2018) BRMS1 Expression in Surgically Resected Lung Adenocarcinoma Predicts Future Metastases and Is Associated with a Poor Prognosis. J Thorac Oncol 13:73-84
Chudgar, Neel P; Brennan, Murray F; Tan, Kay See et al. (2017) Is Repeat Pulmonary Metastasectomy Indicated for Soft Tissue Sarcoma? Ann Thorac Surg 104:1837-1845
Chudgar, Neel P; Brennan, Murray F; Munhoz, Rodrigo R et al. (2017) Pulmonary metastasectomy with therapeutic intent for soft-tissue sarcoma. J Thorac Cardiovasc Surg 154:319-330.e1
Liu, Yuan; Amin, Elianna B; Mayo, Marty W et al. (2016) CK2?' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation. Cancer Res 76:2675-86
Ripley, R Taylor; Suzuki, Kei; Tan, Kay See et al. (2016) Postinduction positron emission tomography assessment of N2 nodes is not associated with ypN2 disease or overall survival in stage IIIA non-small cell lung cancer. J Thorac Cardiovasc Surg 151:969-77, 979.e1-3
Yeh, Yi-Chen; Kadota, Kyuichi; Nitadori, Jun-ichi et al. (2016) International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification predicts occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma. Eur J Cardiothorac Surg 49:e9-e15
Mayor, Marissa; Yang, Neng; Sterman, Daniel et al. (2016) Immunotherapy for non-small cell lung cancer: current concepts and clinical trials. Eur J Cardiothorac Surg 49:1324-33
Kadota, Kyuichi; Sima, Camelia S; Arcila, Maria E et al. (2016) KRAS Mutation Is a Significant Prognostic Factor in Early-stage Lung Adenocarcinoma. Am J Surg Pathol 40:1579-1590
Kadota, Kyuichi; Nitadori, Jun-Ichi; Ujiie, Hideki et al. (2015) Prognostic Impact of Immune Microenvironment in Lung Squamous Cell Carcinoma: Tumor-Infiltrating CD10+ Neutrophil/CD20+ Lymphocyte Ratio as an Independent Prognostic Factor. J Thorac Oncol 10:1301-1310

Showing the most recent 10 out of 35 publications