Inhibition of DHODH Enhances Replication-Associated Genomic Instability and Promotes Sensitivity in Endometrial Cancer.

ABSTRACT: Endometrial carcinoma (EC) is the most common gynecological malignancy in the United States. De novo pyrimidine synthesis pathways generate nucleotides that are required for DNA synthesis. Approximately 38% of human endometrial tumors present with an overexpression of human dihydroorotate dehydrogenase (DHODH). However, the role of DHODH in cancer cell DNA replication and its impact on modulating a treatment response is currently unknown. Here, we report that endometrial tumors with overexpression of DHODH are associated with a high mutation count and chromosomal instability. Furthermore, tumors with an overexpression of DHODH show significant co-occurrence with mutations in DNA replication polymerases, which result in a histologically high-grade endometrial tumor. An in vitro experiment d

SUBMITTER: Zhao S 

PROVIDER: S-EPMC10741824 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature