RUNX3 enhances TRAIL-induced apoptosis by upregulating DR5 in colorectal cancer

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RUNX3 is frequently inactivated by DNA hypermethylation in numerous cancers. Here, we show that RUNX3 has an important role in modulating apoptosis in immediate response to tumor necrosis factor-related apoptosis-including ligand (TRAIL). Importantly, no combined effect of TRAIL and RUNX3 was observed in non-cancerous cells. We investigated the expression of the death receptors (DRs) DR4 and DR5, which are related to TRAIL resistance. Overexpression of RUNX3 increased DR5 expression via induction of the reactive oxygen species (ROS)-endoplasmic reticulum (ER) stress-effector CHOP. Reduction of DR5 markedly decreased apoptosis enhanced by the combined therapy of TRAIL and RUNX3. Interestingly, RUNX3 induced reactive oxygen species production by inhibiting SOD3 transcription via binding to the Superoxide dismutase 3 (SOD3) promoter. Additionally, the combined effect of TRAIL and RUNX3 decreased tumor growth in xenograft models. Our results demonstrate a direct role for RUNX3 in TRAIL-induced apoptosis via activation of DR5 and provide further support for RUNX3 as an anti-tumor.

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This work was supported by a National Research Foundation (NRF) of Korea grant funded the Korean government (MSIP) [NRF-2017R1A6A3A11030765] and was supported by Korea University Grant and was supported by project for cooperative R&D between Industry, Academy, and Research Institute funded Korea ministry of SMES and Startups in 2018 [Grants No. Co558375].

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Correspondence to Sang Cheul Oh or Dae-Hee Lee.

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