TYMS promotes genomic instability and tumor progression in Ink4a/Arf null background

We previously showed that elevated TYMS exhibits oncogenic properties and promotes tumorigenesis after a long latency, suggesting cooperation with sequential somatic mutations. Here we report the cooperation of ectopic expression of human TYMS with loss of Ink4a/Arf, one of the most commonly mutated somatic events in human cancer. Using an hTS/Ink4a/Arf(-/-) genetically engineered mouse model we showed that deregulated TYMS expression in Ink4a/Arf null background accelerates tumorigenesis and metastasis. In addition, tumors from TYMS-expressing mice were associated with a phenotype of genomic instability including enhanced double strand DNA damage, aneuploidy and loss of G1/S checkpoint. Downregulation of TYMS in vitro decreased cell proliferation and sensitized tumor cells to antimetabolite chemotherapy. In addition, depletion of TYMS in vivo by TYMS shRNA reduced tumor incidence, delayed tumor progression and prolonged survival in hTS/Ink4a/Arf(-/-) mice. Our data shows that activation of TYMS in Ink4a/Arf null background enhances uncontrolled cell proliferation and tumor growth, supporting the development of new agents and strategies targeting TYMS to delay tumorigenesis and prolong survival.

Automated summary

We found that elevated expression of TYMS has oncogenic properties and promotes tumorigenesis, suggesting cooperation with sequential somatic mutations. In this study, we demonstrate the cooperation between ectopic expression of human TYMS and loss of Ink4a/Arf, a commonly mutated event in human cancer. Our data shows that deregulated TYMS expression accelerates tumorigenesis and metastasis in an Ink4a/Arf null background. In addition, downregulation of TYMS decreases cell proliferation and sensitizes tumor cells to chemotherapy, while depletion of TYMS reduces tumor incidence, delays tumor progression, and prolongs survival.