TGFβ Promotes Genomic Instability after Loss of RUNX3

Cancer Research
Vaidehi KrishnanYoshiaki Ito

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 sig...Continue Reading

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Citations

Mar 13, 2020·Journal of Cellular Biochemistry·Xun SunTing Wang
Apr 24, 2020·Journal of the National Cancer Institute·Peter T CampbellUlrike Peters
Feb 13, 2018·BMB Reports·Sarala Manandhar, You Mie Lee
Aug 30, 2018·Trends in Molecular Medicine·Yu SunEric W-F Lam
Mar 24, 2021·Developmental Cell·Yoko Katsuno, Rik Derynck

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