RUNX3 methylation drives hypoxia-induced cell proliferation and antiapoptosis in early tumorigenesis

Sun Hee Lee, Do Young Hyeon, Soo Hyun Yoon, Ji Hak Jeong, Saeng Myung Han, Ju Won Jang, Minh Phuong Nguyen, Xin Zi Chi, Sojin An, Kyung gi Hyun, Hee Jung Jung, Ji Joon Song, Suk Chul Bae, Woo Ho Kim, Daehee Hwang, You Mie Lee

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Inactivation of tumor suppressor Runt-related transcription factor 3 (RUNX3) plays an important role during early tumorigenesis. However, posttranslational modifications (PTM)-based mechanism for the inactivation of RUNX3 under hypoxia is still not fully understood. Here, we demonstrate a mechanism that G9a, lysine-specific methyltransferase (KMT), modulates RUNX3 through PTM under hypoxia. Hypoxia significantly increased G9a protein level and G9a interacted with RUNX3 Runt domain, which led to increased methylation of RUNX3 at K129 and K171. This methylation inactivated transactivation activity of RUNX3 by reducing interactions with CBFβ and p300 cofactors, as well as reducing acetylation of RUNX3 by p300, which is involved in nucleocytoplasmic transport by importin-α1. G9a-mediated methylation of RUNX3 under hypoxia promotes cancer cell proliferation by increasing cell cycle or cell division, while suppresses immune response and apoptosis, thereby promoting tumor growth during early tumorigenesis. Our results demonstrate the molecular mechanism of RUNX3 inactivation by G9a-mediated methylation for cell proliferation and antiapoptosis under hypoxia, which can be a therapeutic or preventive target to control tumor growth during early tumorigenesis.

Original languageEnglish
Pages (from-to)1251-1269
Number of pages19
JournalCell Death and Differentiation
Volume28
Issue number4
DOIs
StatePublished - Apr 2021

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