The recent paradoxical dual citizenships of Runt-related transcription factor 3 (Runx3) in tumorigenesis remains poorly characterized. Here, we report the oncogenic capacity of Runx3 as chromatin modulator in metastatic gastric cancer model. Runx3 exists as homodimer and binds cooperatively to modified nucleosomes. Additionally, we detected a synergistic functional enhancement of octamer transfer, nucleosome sliding and stochiometric integrity of SWI/SNF by Runx3. We found that Runx3 depletion increased nucleosomes occupancy and promoted chromatin silencing by heterochromatin condensation and HP1 oligomerization. ATAC-seq analysis revealed differential accessibility per chromosome due to Runx3 null expression with dysregulation of multiple inflammatory response and DNA repair pathways. Mechanistically, these modulations resulted in aberrant DNA damage repair response, which is rescued by RUNX3 overexpression. These findings reveal a new paradigm in Runx3 biology as dynamic chromatin regulatory element vital for the maintenances of cancerous phenotype.

Significance To the best of our knowledge, the present study is the first to explore the role of Runx3 as homodimeic chromatin binding factor and establishes its oncogenic-function as modulator of heterochromatin de-condensation and SWI/SNF chromatin remodeling activities. These emerging features of Runx3 at the epigenetic level imply a promising direction to screen for anti-Runx3 epigenetic drugs “Epi-drugs” in search of novel gastric cancer treatment.

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