Mechanisms Of MEN1 Inactivated Triggers Abnormal DNA Damage Response And Occurrence Of Lung Cancer

Lung cancer is one of the malignant tumors that seriously threaten human health and life,its morbidity and mortality rate rank first among all cancers.Radiotherapy and chenmotherapy are still the main therapeutic regimes for lung cancer,but cancer cells resistance to DNA-damaging chemotherapy and radiotherapy has strongly affects the therapeutic of patients.Abnormal activation of DNA repair is the mian cause of radiresistance,and so inhibitors of targeted DNA repair were developed and used to sensitize cancer cells to therapy is a novel therapy strategy for lung cancer.Deletion or inactivation of MEN1 gene,a key pathogenic gene of the multiple endocrine neoplasia type 1(MEN1),leads to genome instability and occurrence of lung cancer,but its etiology remains unclear.Dysfunctional DNA damage response(DDR)is one of the main causes of genomic instability and tumorigenesis.Menin,the encoding product of MEN1 gene,interacted with various DNA repair factors and involved in DNA damage repair.However,the patterns and biological significance of menin regulating DNA damage repair is still unknown.Researches were conducted base on the above scientific issues and the mouse models including systemic Men1-knockouted and specific alveolar type ? dermal cell KrasG12D mutation-induced spontaneous lung adenocarcinoma,and cell lines with menin deleted were constructed in present study.Our findings shown that:(1)Mutation rate of MEN1 in lung adenocarcinoma is 1%5%;mutation of MEN1 is a higher risk factor than p53 mutation and can be used as a potential marker for tumor typing of lung adenocarcinoma;(2)loss of Men1 leads to occurrence of lung cancer and aggravates the formation of ionizing radiation(IR)induced DNA double-strand break(DSB),and the accumulation of spontaneous DNA damage resulting in genomic instability;(3)Menin deletion abnormal activates homologous recombination(HR)and non-homologous end joining(NHEJ)repair and inhibits cellular senescence,and leads to radioresistance;(4)Menin/MLL recruits to DNA damage sites and increases the modification of chromatin H3K4me3 and deletion of menin leads to disordered chromosome remodeling and blocks HR or NHEJ repair factors recruits to DNA damage sites and further inhibits activity of HR or NHEJ repair;(5)Menin is an upstream regulator of p53 pathway and menin regulates ?-TrCPmediated ubiquitination and protein stability of MDM2/p53 through epigenetic mechanisms,and menin maintains genomic stability by regulating p53-dependent HR and p53-independent NHEJ repair;(6)Menin is a key regulator for cellular senescence,and menin regulates p16 expression through epigenetic mechanisms and further control senescence programs;(7)Menin is required for oncogene KrasG12D mutated activationinduced senescence(OIS),and Men1-deleted lung adenocarcinoma cells escape OIS program to initiate and accelerate development of lung adenocarcinoma.(8)Menin/MLL complex mediated-chromatin H3K4me3 modification is required for cellular senescence and targeting LSD1 histone demethylase inhibitor can partially eliminate the accumulation of DNA damage caused by Men1/MLL deletion and restore the malignant phenotype of lung adenocarcinoma induced by KrasG12D mutation and inhibition of cellular senescence caused by Men1 deletion.Our study explored the chromatin remodeling mechanism that menin regulating DNA damage repair and providing theoretical basis for developing a radiosensitizer to treat lung cancer with menin as target.The study preliminarily explained the relationship between DNA damage repair regulated by menin,cellular senescence and radioresistance,and improved people's understanding of MEN1 biological function.The present study reveals the mechanism that MEN1 maintaining genomic stability and inhibiting tumorigenesis.LSD1 inhibitor is expected to be a potential drug for the treatment of tumor with menin inactivated.