KCNJ15 inhibits chemical-induced lung carcinogenesis and progression through GNB1 mediated Hippo pathway.

Abstract

Polycyclic aromatic hydrocarbons (PAHs) have been regarded as important environmental carcinogens that can cause lung cancer. However, the underlying epigenetic mechanism during PAHs-induced lung carcinogenesis has remained largely unknown. Previously, we screened some novel epigenetic regulatory genes during 3-methylcholanthrene (3-MCA)-induced lung carcinogenesis, including the potassium inwardly rectifying channel subfamily J member 15 (KCNJ15) gene. This study aimed to investigate the expression regulation, function, and mechanism of KCNJ15 through database analysis, malignant transformed cell model, and xenograft tumor models. We found that KCNJ15 was remarkably under-expressed during lung carcinogenesis and progression. Elevated levels of DNA methylation were associated with a gradual decrease of KCNJ15 expression in 3-MCA-induced malignantly transformed HBE cells. High expression of KCNJ15 was strongly correlated with good survival prognosis in lung cancer patients. KCNJ15 overexpression significantly inhibited the growth, invasion, and migration of lung cancer cells both in vitro and in vivo. Conversely, knockdown of KCNJ15 resulted in an opposite phenotype. Moreover, KCNJ15 inhibited the Hippo pathway by activating YAP phosphorylation and inhibiting YAP expression. Mechanistically, there was a significant protein-protein interaction between KCNJ15 and the G protein subunit beta 1 (GNB1). GNB1 overexpression partially restored the inhibition of Hippo pathway regulated by KCNJ15. In summary, our data demonstrated that KCNJ15, as a novel epigenetic silencing tumor suppressor, regulates cell growth, invasion, and migration by binding to GNB1 protein mediating the Hippo-YAP signaling pathway during chemical-induced lung carcinogenesis and progression. It provides novel insights into epigenetic regulation mechanism during carcinogenesis induced by environmental pollutants.