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TGFβ Promotes Genomic Instability after Loss of RUNX3
Vaidehi Krishnan1, Yu Lin Chong2, Tuan Zea Tan2
1Cancer Science Institute of Singapore, National University of Singapore, Singapore. csiitoy@nus.edu.sg bchtjp@nus.edu.sg csivk@nus.edu.sg.
Abstract:
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. Cancer Res; 78(1); 88-102. ©2017 AACR.
Insights
RUNX3 loss in cancer cells removes an antioxidant defense, allowing TGFβ from the tumor microenvironment to induce DNA damage and genomic instability, promoting tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Genomic instability research has historically overlooked extrinsic factors in the tumor microenvironment (TME).
- Transforming growth factor beta (TGFβ) is a key TME cytokine driving cancer aggressiveness, including invasion, drug resistance, and epithelial-to-mesenchymal transition (EMT).
Purpose of the Study:
- To investigate the role of TGFβ in promoting genomic instability within the TME.
- To elucidate the mechanism by which RUNX3 loss influences TGFβ-induced DNA damage and cancer progression.
Main Methods:
- Analysis of DNA double-strand breaks (DSB) in cancer cells with and without RUNX3.
- Assessment of heme oxygenase-1 (HO-1/HMOX1) expression and its role as a redox regulator.
- Evaluation of oxidative DNA damage, cellular senescence, and senescence-associated secretory phenotype (SASP) markers.
- Correlation of TGFβ gene expression signatures and RUNX3 loss with genomic instability in tumors.
Main Results:
- TGFβ induces DNA double-strand breaks (DSB) in cancer cells lacking the RUNX3 tumor suppressor.
- RUNX3 loss leads to reduced heme oxygenase-1 (HO-1) expression, impairing the antioxidant response.
- Elevated oxidative DNA damage triggers cellular senescence and the pro-tumorigenic senescence-associated secretory phenotype (SASP).
- Tumors with both TGFβ signatures and RUNX3 loss exhibit significantly higher genomic instability.
Conclusions:
- RUNX3 acts as a critical barrier against TGFβ-driven genomic instability and tumor progression.
- RUNX3 inactivation cooperates with extrinsic TGFβ signaling to exacerbate genomic instability in cancer.
- Restoring RUNX3 function may represent a therapeutic strategy to counteract TGFβ-induced DNA damage in the TME.
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