RUNX3 suppresses metastasis and stemness by inhibiting Hedgehog signaling in colorectal cancer
- Kim, Bo Ram; Na, Yoo Jin; Kim, Jung Lim; Jeong, Yoon A.; Park, Seong Hye; Jo, Min Jee; Jeong, Soyeon; Kang, Sanghee; Oh, Sang Cheul; Lee, Dae-Hee
- Issue Date
- Nature Publishing Group
- Cell Death and Differentiation, v.27, no.2, pp.676 - 694
- Journal Title
- Cell Death and Differentiation
- Start Page
- End Page
- Disabled tumor suppressor genes and hyperactive oncogenes greatly contribute to cell fates during cancer development because of their genetic alterations such as somatic mutations. However, little is known about how tumor suppressor genes react to diverse oncogenes during tumor progression. Our previous study showed that RUNX3 inhibits invasiveness by preventing vascular endothelial growth factor secretion and suppressed endothelial cell growth and tube formation in colorectal cancer (CRC). Hedgehog signaling is crucial for the physiological maintenance and self-renewal of stem cells, and its deregulation is responsible for their tumor development. The mechanisms that inhibit this pathway during proliferation remain poorly understood. Here, we found that the tumor suppressor RUNX3 modulates tumorigenesis in response to cancer cells induced by inhibiting oncogene GLI1 ubiquitination. Moreover, we demonstrated that RUNX3 and GLI1 expression were inversely correlated in CRC cells and tissues. We observed a direct interaction between RUNX3 and GLI1, promoting ubiquitination of GLI1 at the intracellular level. Increased ubiquitination of GLI1 was induced by the E3 ligase beta-TrCP. This novel RUNX3-dependent regulatory loop may limit the extent and duration of Hedgehog signaling during extension of the tumor initiation capacity. On the basis of our results, identification of agents that induce RUNX3 may be useful for developing new and effective therapies for CRC.
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- 3. Graduate School > Graduate School > 1. Journal Articles
- 2. Clinical Science > Department of Medical Oncology and Hematology > 1. Journal Articles
- 2. Clinical Science > Department of Colon and Rectal Surgery > 1. Journal Articles
- 4. Research institute > Institute of Convergence New Drug Development > 1. Journal Articles
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