JQ1 Downregulates Met Expression And Inhibits The Growth Of Non-small Cell Lung Carcinoma Cells

Lung cancer is one of the most common malignant tumors that threatening the people's health,its morbidity and mortality are on the top of cancer related deaths.Despite the early diagnosis and standard treatments have made some progress,most of the patients are diagnosed at middle-late stage and have lost the opportunity for surgery;therefore,chemotherapy and molecular-targeted therapy are important in treatment of non-small cell lung carcinoma(NSCLC).JQ1 is a small molecule inhibitor of BET(bromodomain and extra terminal domain)protein family with the strongest inhibitory effect on BRD4.BRD4can specifically identify and physically bindtothe acyelylated lysine residues of chromatin histone H3/H4 to regulate gene transcription.It plays an important rolein cell cycle progression,DNA replication,and gene reconstruction.It has been shown to promote the development of cancer.JQ1 is very effective for leukemia and multiple myeloma,and it also inhibits the growth of various solid tumors,such as ovarian cancer,breast cancer,hormone resistant prostate cancer,and glioblastoma.However,for the effect and mechanism of JQ1 on non-small cell lung carcinoma are far from being elucidated.Epidermal growth factor receptor tyrosine kinase inhibitors,such as Erlotinib and Gefitinib,have become the standard treatment of advanced non-small cell lung carcinoma,but development of the acquired resistance is a major problem in clinic.Met overexpression is one of the important mechanisms for the acquired resistance of NSCLC.Therefore,identifying new therapeutic targets and developing new anticancer medicines are urgently needed for the treatment of NSCLCs.In this study,we explored the effect and mechanism of JQ1 on the growth of NSCLCs.We found that JQ1 inhibited a variety of human NSCLC cells,including A549,H157,Calu-1,and H460.It significantly downregulated the mRNA and protein levels of Met and subsequently inhibited PI3K/Akt and MAPK/ERK signaling pathway,which are two major downstream signaling papthways of Met.HGF(hepatocyte growth factor),as a ligand of Met,activated PI3K/Akt and MAPK/ERK signaling pathways and promoted cell growth.JQ1 can reducethe effects of HGF by downregulation of Met expression.Moreover,JQ1 significantly inhibited the growth of erlotinib sensitive and resistance cells in parallel with downregulation of Met expression and inhibition of the PI3K/Akt and MAPK/ERK signaling pathways.Finally,JQ1 inhibited the growth of H460 and erlotinib resistant HCC827 tumors in nude mice models in parallele with downregulation of Met expression.These results suggest that JQ1 reduced Met expression,downregulated PI3K/AKT and MAPK/ERK signaling pathways,and inhibited the growth of NSCLCs.It extends our understanding of JQ1's effects and mechanisms,provides new clues for the treatment of NSCLCs and erlotinib resistace.