Role of IKK in NSCLC: Modulation of SMRT and NF-kappaB


Principal Investigator: Marty W Mayo
Abstract: Lung cancer is the number one cancer killer in the United States, exceeding breast, colorectal, prostate, and melanoma malignancies combined. Of all newly diagnosed lung cancers, greater than eighty percent of these malignancies are non-small cell lung cancer (NSCLC). NF-?B is a transcription factor that plays a key role in the activation of genes involved in cancer initiation and progression. NF-?B activity in human tumors is associated with dedifferentiated NSCLC morphology, advanced tumor stage, and poor clinical outcomes. The tumor microenvironment is responsible for stimulating a morphogenesis within carcinoma cells referred to as epithelial to mesenchymal transition (EMT). EMT is believed to be essential to carcinoma progression by stimulating invasion and metastasis. Although NF-?B has been shown to be required for EMT, the importance of this regulation is poorly understood. Our laboratory has developed a novel EMT system that allows NSCLC cells to achieve 100% transition. Induction of EMT in NSCLC cells greatly increases migration, invasion, and lung metastasis, resulting in constitutive NF-?b transcriptional activity. Inhibition of NF-?B prevents NSCLC cells from undergoing EMT, indicating that NF-?B plays a direct role in the EMT process. The induction of EMT stimulates the expression of master-switch transcription factors, including Twist, and increases the expression of the polycomb repressive complex (PRC) proteins, which are critical for initiation and maintenance of stem-like phenotypes. Mesenchymal NSCLC cells require NF-?B to upregulate critical components of the PRC, while differentially repressing others. NF-?B stimulates gene expression of PRC proteins by recruiting IKK1 and PCAF to responsive promoters and derepressing SMRT (silencing mediator for retinoid and thyroid hormone receptors) and histone deacetylase (HDAC)3 corepressor complexes. In contrast, Twist and NF-?B actively repress other gene targets by stable recruitment of SMRT/HDAC3. Here, we provide the first evidence associating NF-?B with an increase in epigenetic modifications associated with cancer progenitor cells. The main goal of this proposal is to identify NF-?B regulated genes that encode epigenetic effectors responsible for initiating reprogramming of cancer progenitor cells. To address our hypothesis, three specific aims will be addressed. Aim 1 will identify NF-?B regulated genes that coordinate epigenetic reprogramming in cancer progenitor cells using genome-wide analysis. Aim 2 will determine the role of p65 as an activator or repressor of polycomb-mediated gene expression. Aim 3 will examine the role of NF-?B in epigenetic reprogramming using human tumor tissues and lung metastasis models. Identifying the importance of NF-?B in regulating key factors that govern epigenetic reprogramming in cancer progenitor cells will potentially lead to the discovery of novel therapeutic targets for the diagnosis and treatment of lung cancer. PUBLIC HEALTH RELEVANCE: A major focus in biomedical research is to understand how cancer cells invade healthy cells and metastasize to distant sites. Lung cancer in particular is more prone to aggressive forms of the disease that are difficult to treat effectively and have a poor clinical prognosis. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. The 5-year mean survival for patients suffering from stage III lung cancer is less than 30%. Poor clinical prognosis for NSCLC is directly associated with late-stage diagnosis and high propensity for metastasis to liver and bone. For the last several years our laboratory has been working on a transcription factor called nuclear factor-kappa B (NF-?B). NF-?B is a protein complex that is found in almost all human cells. In non-cancerous cells NF-?B is tightly regulated, however, cancer cells have found ways to elevate the activity of NF-?B. Although it is known that cancer cells enhance NF-?B activity, the reasons for this are not fully understood. Our laboratory has discovered that NF-?B is one of the master-switch transcription factors required to induce phenotypic changes in cells referred to as epithelial to mesenchymal transition (EMT). EMT is a critical step in cancer metastasis. For the first time, our laboratory can demonstrate that following the induction of EMT, NF-?B is required to orchestrate changes associated with the induction and maintenance of cancer stem cells. Cancer stem cells are believed to act as a "seed" which is able to reestablish malignant disease. This proposal will identify critical EMT-induced genes that are required for induction and maintenance of cancer stem cells. The overall goal of this project is use these newly identified gene products as novel therapeutic targets for detection and treatment of NSCLC.
Funding Period: 2004-04-19 - 2013-08-31
more information: NIH RePORT