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 #
5R01CA136705-04
Application #
8294448
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
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$304,932
Indirect Cost
$103,657
Name
University of Virginia
Department
Surgery
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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
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
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
Liu, Yuan; Amin, Elianna B; Mayo, Marty W et al. (2016) CK2α' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation. Cancer Res 76:2675-86
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
Buitrago, Daniel H; Patnaik, Santosh K; Kadota, Kyuichi et al. (2015) Small RNA sequencing for profiling microRNAs in long-term preserved formalin-fixed and paraffin-embedded non-small cell lung cancer tumor specimens. PLoS One 10:e0121521
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 10:1301-10
Kadota, Kyuichi; Yeh, Yi-Chen; Villena-Vargas, Jonathan et al. (2015) Tumor Budding Correlates With the Protumor Immune Microenvironment and Is an Independent Prognostic Factor for Recurrence of Stage I Lung Adenocarcinoma. Chest 148:711-21
Ujiie, Hideki; Kadota, Kyuichi; Chaft, Jamie E et al. (2015) Solid Predominant Histologic Subtype in Resected Stage I Lung Adenocarcinoma Is an Independent Predictor of Early, Extrathoracic, Multisite Recurrence and of Poor Postrecurrence Survival. J Clin Oncol 33:2877-84
Kadota, Kyuichi; Eguchi, Takashi; Villena-Vargas, Jonathan et al. (2015) Nuclear estrogen receptor-α expression is an independent predictor of recurrence in male patients with pT1aN0 lung adenocarcinomas, and correlates with regulatory T-cell infiltration. Oncotarget 6:27505-18

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