Krishnan V1, Chong YL2, Tan TZ2, Kulkarni M2,3, Bin Rahmat MB2, Tay LS2, Sankar H2, Jokhun DS4,5, Ganesan A2, Chuang LSH2, Voon DC2, Shivashankar GV4,5, Thiery JP6,7, Ito Y1.
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
3 Lee Kong Chian School of Medicine, NTU, Singapore.
4 Mechanobiology Institute, National University of Singapore, Singapore.
5 Department of Biological Sciences, National University of Singapore, Singapore.
6 Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
7 UMR 1186 INSERM Institute, Gustave Roussy, Villejuif, France.
Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based in the tumor microenvironment (TME). TGFβ 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 TGFβ also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells that 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 harboring a TGFβ gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGFβ-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell-extrinsic TGFβ signaling and cancer cell-intrinsic RUNX3 inactivation as aggravating factors for genomic instability. Significance: RUNX3 inactivation in cancer removes an antioxidant barrier against DNA double strand breaks induced by TGFβ expressed in the tumor microenvironment. ©2017 AACR.