The leading cause of cutaneous squamous cell carcinomas (cSCCs) is exposure to ultraviolet radiation (UV). Unlike most other cancers, the incidence rates of cSCCs are still on the rise and the treatment options currently available are limited. We have recently found that dihydroorotate dehydrogenase (DHODH), which is the rate-limiting enzyme in the de novo pyrimidine synthesis pathway, plays a critical role in UVB-induced energy metabolism reprogramming. Using a multistage model of UVB radiation-induced skin cancer, we show that UVB-induced DHODH upregulation is mainly regulated transcriptionally by STAT3. Our results indicate that chronic inhibition of DHODH by leflunomide (LFN) blocks UVB-induced tumor initiation. Human tumor xenograft studies showed that LFN treatment reduces growth of established tumors when used in combination with a genotoxic agent, 5-fluorouracil (5-FU). Our data suggest that DHODH is a promising target for chemoprevention and combination therapy of UVB-induced cSCCs.

皮肤鳞状细胞癌（cSCCs）的主要原因是暴露于紫外线辐射（UV）。与大多数其他癌症不同，cSCC的发病率仍在上升，目前可用的治疗选择有限。我们最近发现二氢乳清酸脱氢酶（DHODH）是从头嘧啶合成途径中的限速酶，在UVB诱导的能量代谢重编程中起关键作用。使用UVB辐射诱导的皮肤癌的多阶段模型，我们显示UVB诱导的DHODH上调主要是由STAT3转录调控的。我们的结果表明，来氟米特（LFN）对DHODH的长期抑制作用会阻止UVB诱导的肿瘤发生。人类肿瘤异种移植研究表明，与基因毒性药物5-氟尿嘧啶（5-FU）组合使用时，LFN治疗可减少已建立肿瘤的生长。我们的数据表明DHODH是化学预防和UVB诱导的cSCC联合治疗的有希望的靶标。