Investigating the Therapeutic Potential of MDM2 and DNMTs Inhibition in Non-Small Cell Lung Cancer

Investigating the Therapeutic Potential of MDM2 and DNMTs Inhibition in Non-Small Cell Lung Cancer

Alvin Sherman Library

Lung cancer is one of the leading causes of cancer-related deaths, underscoring the need for more effective therapeutic strategies. This study explores the impact of MDM2 and DNMTs inhibition on key regulatory pathways in the HCC827 lung cancer cells, specifically focusing on epigenetic modification and cell cycle regulation. We investigated the effects of RG-7388 (MDM2 inhibitor) and CM-272 (G9a/DNMTs inhibitor) on MRNAs and miRNAs gene expressions that were suspected to be modulating the above-mentioned processes. Our qRT-PCR results showed significant downregulation of epigenetic modifiers (DNMT1, DNMT3A, DNMT3b) and cell cycle arrest genes (CDC25A, CDC25C) in both RG-7388 and CM-272 treated groups compared to controls. Furthermore, TaqMan® Advanced miRNA Assays revealed that RG-7388 and CM-272 treatments upregulated several miRNAs, including hsa-miR-652-3p, hsa-miR-208b-3p, hsa-miR-200c-3p, hsa-miR-181d-5p, hsa-miR-744-5p, hsa-miR-181a-5p, hsa-let-7i-5p, and hsamiR-200c-3p. In addition, these treatments downregulated the following miRNAs, such as hsa-miR-651-5p and hsa-miR-197-3p. These mRNA and miRNAs have been implicated in lung cancer growth and progression, by regulating DNA methylation, histone modification, cell cycle arrest, and cell proliferation. In summary, our study highlights the potential of RG-7388 and CM-272 to induce epigenetic alterations in lung cancer cells (HCC827) by downregulating DNA methyltransferase and cell cycle regulation gene expressions. These findings have implications for the development of effective therapeutic strategies for lung cancer. (This project was supported by the President's Faculty Research and Development Grant (PFRDG), and by the Royal Dames of Cancer Research Inc. Ft. Lauderdale, Florida).