TGFβ Promotes Genomic Instability after Loss of RUNX3

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 1; pp. 88 - 102
• Main Authors: Krishnan, Vaidehi, Chong, Yu Lin, Tan, Tuan Zea, Kulkarni, Madhura, Bin Rahmat, Muhammad Bakhait, Tay, Lavina Sierra, Sankar, Haresh, Jokhun, Doorgesh S, Ganesan, Amudha, Chuang, Linda Shyue Huey, Voon, Dominic C, Shivashankar, G V, Thiery, Jean-Paul, Ito, Yoshiaki
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 01.01.2018
• Subjects: Antioxidants; Cancer; Cytokines; Deoxyribonucleic acid; DNA; DNA damage; Double-strand break repair; Drug resistance; Gene expression; Genomic instability; Heme; Heme oxygenase (decyclizing); Historical account; Inactivation; Inflammation; Invasiveness; Mesenchyme; Oxygenase; Phenotypes; Runx3 protein; Senescence; Transcription; Tumor suppressor genes; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-1178

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 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. RUNX3 inactivation in cancer removes an antioxidant barrier against DNA double strand breaks induced by TGFβ expressed in the tumor microenvironment. .