Role of KAT5 in lung cancer
Embargo Date
2025-02-13
OA Version
Citation
Abstract
Lung cancer is the leading cause of global cancer mortality. Recent investigations and discoveries of genetic alterations in Epidermal Growth Factor Receptors (EGFR) have led to the development of tyrosine kinase inhibitors (TKIs) as possible lung cancer therapies. However, intrinsic and acquired resistance to drug therapies currently serve as a major problem when treating patients diagnosed with lung cancer. Histone modifications, like lysine acetylation performed by lysine acetyltransferases (KATs), play important roles in transcriptional activation, gene silencing, and other abnormal epigenetic changes that are connected to oncogenesis. Lysine acetyltransferase 5 (KAT5) is expressed at lower levels in multiple lung cancer cell lines as well as clinical lung tumor tissues compared to those of normal. To assess the function of KAT5, we generated lung cancer cells harboring KAT5 overexpression or inducible shRNA against KAT5 (shKAT5) and lung-specific, conditional Kat5 gene knockout (KO) mice. In vitro cell line models showed decreased cell proliferation and cell migration activity in KAT5 knockdown cells; however, no major differences were observed in cells overexpressing KAT5. Consistent with these results, our in vivo experiments demonstrated that homozygous Kat5 knockout lungs (Kat5F/F) had no tumor formation compared to heterozygous knockout (Kat5Wt/F) and wildtype Kat5 (Kat5Wt/Wt) in mice that harbor CCSP-EGFR-T790M (EGFRTL) mutations. Major effector genes downstream of Kat5 were also identified from ribonucleic acid sequencing (RNA-Seq) and Chromatin immunoprecipitation sequencing (ChIP-Seq). One gene identified downstream of Kat5 was TGM5. We then showed that TGM5 contributes to tumor progression and migration. Lastly, anti-malarial drug artemisinin was also shown to suppress tumor progression through downregulation of KAT5 in vitro and in vivo models. We thus propose that artemisinin can be a potent candidate for the treatment of lung cancer as it is tumor-specific and downregulates KAT5.