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.
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.).