Oral squamous cell carcinoma (OSCC) become a heavy burden of public health, with approximately 300 000 newly diagnosed cases and 145 000 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.

口腔鳞状细胞癌（OSCC）已成为公共卫生的沉重负担，全球每年约有30万新诊断病例和14.5万例死亡。核苷酸代谢促进 DNA 复制和 RNA 合成，这对于细胞增殖是必不可少的。但肿瘤细胞如何协调核苷酸代谢酶来支持其快速生长尚不清楚。在这里，我们发现与非癌性邻近组织相比，口腔鳞癌组织中嘧啶代谢酶二氢乳清酸脱氢酶（DHODH）的表达上调。DHODH 表达的增强与患者生存时间的缩短相关。shRNA 或选择性抑制剂对 DHODH 的抑制会损害 OSCC 细胞的增殖和肿瘤异种移植物的生长。此外，功能性 DHODH 的丧失会阻碍嘧啶从头合成，并可能通过破坏 MICOS 复合物的稳定性来破坏线粒体呼吸。机制研究表明转录因子SOX2在OSCC中DHODH的上调中发挥重要作用。我们的研究结果增加了关于癌细胞如何利用核苷酸代谢来支持其快速生长的知识，从而强调 DHODH 作为 OSCC 治疗的潜在预后和治疗靶点。