Krishnan V1, Chong YL2, Tan TZ1, Kulkarni MD3, Bin Rahmat MB4, Tay LS1, Jokhun DS5, Ganesan A6, Chuang LSH4, Voon DC7, Gv S5, Thiery JP8, Ito Y9.
1 Cancer Science Institute of Singapore, National University of Singapore.
2 RUNX lab, Cancer Science Institute of Singapore, NUS.
3 CSI, Cancer Science Institute, NUS.
4 Cancer Science Institute of Singapore, NUS.
5 Mechanobiology Institute, Singapore, National University of Singapore.
6 CSI, Cancer Science Institute of Singapore, NUS.
7 Cancer Research Core, Institute fore Frontier Science Initiative, Kanazawa University.
8 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore.
9 Cancer Biology, Cancer Science Institute of Singapore, NUS firstname.lastname@example.org.
Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based on the tumor microenvironment (TME). TGF-β is the most abundantly secreted cytokine in the TME where it imparts various aggressive characteristics including invasive migration, drug resistance and epithelial-to-mesenchymal transition (EMT). Here we show that TGF-β also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells which lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harbouring a TGF-β gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGF-β-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell-extrinsic TGF-β signaling and cancer cell-intrinsic RUNX3 inactivation as aggravating factors for genomic instability.