SOX2-dependent expression of dihydroorotate dehydrogenase regulates oral squamous cell carcinoma cell proliferation

作     者：Xuemei Qiu Sheng Jiang Yanxuan Xiao Yumin He Tao Ren Lu Jiang Rui Liu Qianming Chen Xuemei Qiu;Sheng Jiang;Yanxuan Xiao;Yumin He;Tao Ren;Lu Jiang;Rui Liu;Qianming Chen

作者机构：State Key Laboratory of Oral Diseases&National Clinical Research Center for Oral Diseases&Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and ManagementWest China Hospital of StomatologySichuan UniversityChengduChina Ministry of science and technologyThe Second Affiliated Hospital of Chengdu Medical College(China National Nuclear Corporation 416 Hospital)ChengduChina Oncology DepartmentClinical Medical College and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina 

出 版 物：《International Journal of Oral Science》 (国际口腔科学杂志（英文版）)

年 卷 期：2021年第13卷第1期

页      面：62-70页

核心收录：

学科分类：1003[医学-口腔医学] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by grant from the CAMS Innovation Fund for Medical Sciences(CIFMS)2019-I2M-5-004(Q.C.) National Natural Science Foundation of China grants 81672674(R.L.),81872218(R.L.)and 81872208(L.J.) Science&Technology Department of Sichuan Province Applied Basic Research Program 2020YJ0451(T.R.) Fok Ying Tong Education Foundation grant 161036(R.L.) Young Talent Program of China National Nuclear Corporation CNNC201948(S.J.) Chengdu Medical College Fund Natural Science General Project CYZ18-17(S.J.). 

主　　题：SOX2 metabolism squamous 

摘      要：Oral squamous cell carcinoma(OSCC)become a heavy burden of public health,with approximately 300000 newly diagnosed cases and 145000 deaths worldwide per year.Nucleotide metabolism fuel DNA replication and RNA synthesis,which is indispensable for cell proliferation.But how tumor cells orchestrate nucleotide metabolic enzymes to support their rapid growth is largely unknown.Here we show that expression of pyrimidine metabolic enzyme dihydroorotate dehydrogenase(DHODH)is upregulated in OSCC tissues,compared to non-cancerous adjacent tissues.Enhanced expression of DHODH is correlated with a shortened patient survival time.Inhibition of DHODH by either shRNA or selective inhibitors impairs proliferation of OSCC cells and growth of tumor xenograft.Further,loss of functional DHODH imped de novo pyrimidine synthesis,and disrupt mitochondrial respiration probably through destabilizing the MICOS complex.Mechanistic study shows that transcriptional factor SOX2 plays an important role in the upregulation of DHODH in OSCC.Our findings add to the knowledge of how cancer cells co-opt nucleotide metabolism to support their rapid growth,and thereby highlight DHODH as a potential prognostic and therapeutic target for OSCC treatment.