KLF4 as a Novel Biomarker and Tumor Suppressor in Lung Cancer - Watt scope

Lung cancer is the leading cause of cancer-related mortality in the US. Multiple genetic and epigenetic factors contribute to lung cancer pathogenesis including KLF4, a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. KLF4 is a putative tumor suppressor in gastrointestinal cancers but also acts as an oncogene in several other cancers. To understand the role of KLF4 in the lung, we generated a tamoxifen-induced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the lung. To understand how KLF4 functions during lung tumorigenesis, we generated a K-rasLSL-G12D/+;Klf4fl/fl mouse model, and we used adenoviruses-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation at eight weeks, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation causes lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed a lung-cancer database from TCGA and found that KLF4 expression was significantly lower in lung tissue from cancer patients than in tissue from normal patients. We analyzed the profiles of KLF4 mutation, promoter methylation and epigenetic factors. We found that class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment. In summary, the Central Hypothesis is that KLF4 regulates normal lung homeostasis and acts as a tumor suppressor for lung cancer. KLF4 is a potential biomarker for lung cancer and small molecules KLF4 activators could be developed as therapeutic agents for lung cancer treatment. To this end, we have two Specific Aims: 1) Delineate the mechanisms of KLF4 as a tumor suppressor for lung cancer using in vitro and in vivo models; and 2) Examine the mechanisms of KLF4 deregulation in lung cancer and test small molecule KLF4 activators for lung cancer treatment.