Runx3 Acts as Novel Modulator of Chromatin Dynamics and DNA Damage Response in Gastric Cancer
Authors
Salma A. Mahmoud1*, Yoshiaki Ito1
Affiliations
- Cancer Science Institute (CSI), National University of Singapore, 14 Medical Dr, #12-01 Centre for Translational Medicine, Singapore 117599
Corresponding Author
Salma A. Mahmoud (a.awad@nus.edu.sg)
Abstract
There has been a great advance in understanding the function of Runt-related transcription factors (RUNX) proteins in cancer, however the dual roles of RUNX3 in tumorigenesis remains not fully understood. In this study we are exploring the oncogenic capacity of RUNX3 as epigenetic modulator gastric cancer cellular model. We found that Runx3 acts as homodimeric nucleosomal binding element enhancing SWI/SNF chromatin remodeling activities. Ablation of RUNX3 represses euchromatin accessibility and promote chromatin silencing by increased condensation, HP1 oligomerization and H3K9 hypermethylation. Additionally, the knockout of RUNX3 lead to massive loss of several SWI/SNF protein subunits and was associated with dysregulation of tumorigenic pathways using ATAC-seq/RNA-seq integration. Mechanistically, abrogation of RUNX3 resulted in activation of DNA damage response that was recused with RUNX3 overexpression. These results reveal a new paradigm on Runx3 role as pioneer heterochromatin boundary element regulating multiple facades of chromatin dynamics with concomitant alteration of cancer growth and new targets for therapeutics.
Keywords
Runx3, Homodimer, Chromatin, Hetrochromatin