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

Bo Ram Kim, Seong Hye Park, Yoon A. Jeong, Yoo Jin Na, Jung Lim Kim, Min Jee Jo, Soyeon Jeong, Hye Kyeong Yun, Sang Cheul Oh, Dae Hee Lee

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23 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)3903-3918
Number of pages16
Issue number20
Publication statusPublished - 2019 May 16

Bibliographical note

Funding Information:
Acknowledgements 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].

Publisher Copyright:
© 2019, Springer Nature Limited.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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