SETDB1 Tumor Suppressor In Malignant Mesothelioma

The histone methyltransferase family is the major regulators of epigenetics.SET domain branch type 1(SETDB1)is a member of the histone methyltransferase family,which mainly causes methylation of the lysine residue at position 9 of histone H3,showing multiple regulatory functions in biological networks involving gene transcriptional inhibition and autosomal gene silencing.Abnormal expression of SETDB 1 is closely related to the occurrence of various diseases,including mental disorders such as Huntington's disease,schizophrenia;tumor diseases such as breast cancer,lung cancer,malignant mesothelioma,prostate cancer and so on.Malignant mesothelioma is a rare and highly lethal malignant thoracic tumor with high invasiveness and poor prognosis.Asbestos exposure is the main pathogenic factor for the occurrence and development of mesothelioma.At present,pleural resection,chemotherapy or radiotherapy have not significantly improved the survival of patients.Studies have shown that SETDB I has certain mutation in mesothelioma cells,but its function is unknown.Therefore,we used western,cell growth,clone formation,glucose consumption and ROS generation to investigate the effects of SETDB1 overexpression on the phenotype of mesothelioma cell,while tumorigenesis were used to investigate tumor formation in nude mice.Secondly,the effects of clinical chemotherapeutic drugs pemetrexed on overexpressing SETDB1 cells were investigated by cell growth and cell clonality experiments.Finallly,we used transcriptome sequencing,co-immunoprecipitation and RNA interference knockdown p53 to explore the regulatory relationship between SETDB I and p53.The results showed that SETDB 1 was mainly expressed in near-haploid mesothelioma,but expressed normally in near-diploid mesothelioma cells.Overexpression of SETDB 1 in near-haploid mesothelioma cells MES0257 and MES0542 can significantly inhibit cell proliferation,cell clonality,glucose metabolism and ROS generation;Pemetrexed was used to treat SETDB 1 overexpressed cell lines.The results showed that they could synergistically inhibit the growth and cloning of mesothelioma cells;Tumor formation in nude mice further demonstrated that overexpression of SETDB 1 inhibited the growth of tumors.Compared with drug testing alone or overexpression of SETDB 1,pemetrexed significantly inhibited the growth of tumors with overexpression of SETDB 1;These results suggest that SETDB I is a tumor suppressor in mesothelioma cells.Next,we found that overexpression of SETDB1 induced up-regulation of p53 at protein level;p53 knockdown resulted in decreased protein expression of SETDB1;co-immunoprecipitation indicated no interaction between SETDB1 and p53.These data suggest that SETDBI acts as a tumor suppressor in malignant mesothelioma and has a positive feedback regulation relationship with p53.These new findings have important clinical implications for the treatment of malignant mesothelioma,and drug targeting SETDB1 may become a new therapeutic strategy.