Molecular Mechanism Of BAP1 Regulates MTOR Signaling Pathway

BAP1 was originally identified as a protein that interacts with BRCA1 by yeast two-hybrid,encoding a nuclear deubiquitlyting enzyme,it belongs to the family of nuclear ubiquitin carboxyterminal hydrolase(UCH),and its known substrates include histone 2A and BARD1.Liver kinase B1(LKB1;also known as STK11)is a serine/threonine protein kinase.LKB1 has been found to play an important role in intracellular homeostasis and tumor suppression.Although the downstream signaling pathway regulated by LKB1 is relatively clear,the mechanism of upstream regulation of LKB1-AMPK-mTOR has long been unclear.This study found that LKB1 and BAP1 interact through yeast two-hybrid technology,and the existence of the interaction were also verified in 293 T cells.Further research found that deubiquitination of LKB1 by BAP1,both of which are mainly located in the nucleus.BAP1 protein levels correlated well with AMPK phosphorylation levels in several lung cancer cell lines.In vitro,phosphorylation experiments also suggested that BAP1 stimulated more AMPK phosphorylation by LKB1.Overexpression of BAP1 can significantly inhibit cell growth,knocking down LKB1 can alleviate this strong inhibitory effect,at the same time,BAP1 knockdown also showed a higher level of S6K1 phosphorylation.S6K1 is a mTOR substrate protein.The mTOR inhibitor rapamycin can significantly inhibit cell transformation caused by BAP1 knockdown.In kidney cancer cells with BAP1 knockdown,we observed more lipid accumulation.Given that lipid and cholesterol synthesis is controlled by LKB1-AMPK-mTOR,cells with BAP1 knockdown inhibited mTOR inhibitor and HMG-Co A Tolerance of the agent,all our results suggest the BAP1-LKB1-AMPK-mTOR signaling pathway.BAP1's involvement in apparent regulation and DNA repair can explain why BAP1-deficient tumor cells are prone to malignant transformation.However,whether and how BAP1 regulates other major cancer promotion pathways has not been fully studied.This work provides molecular mechanism for deubiquitinase BAP1 to regulate mTOR signaling pathway.Provide a new perspective for personalized clinical treatment of BAP1-deficient tumors.