Aberrant Upregulation of RUNX3 Activates Developmental Genes to Drive Metastasis in Gastric Cancer (Cancer Research Communications – AACR Journals, Jan 2024)

Kazuto Suda 1Atsushi Okabe 2Junichi Matsuo 1Linda Shyue Huey Chuang 1Ying Li 1Nawaphat Jangphattananont 1Naing Naing Mon 1Khine Nyein Myint 1Akihiro Yamamura 1Jimmy Bok-Yan So 3Dominic Chih-Cheng Voon 4Henry Yang 1Khay Guan Yeoh 5 6Atsushi Kaneda 2Yoshiaki Ito 1

Affiliations

  • 1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • 2Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • 3Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 4Innovative Cancer Model Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Japan.
  • 5Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 6Department of Gastroenterology and Hepatology, National University Health System, Singapore.

Abstract

Gastric cancer metastasis is a major cause of mortality worldwide. Inhibition of RUNX3 in gastric cancer cell lines reduced migration, invasion, and anchorage-independent growth in vitro. Following splenic inoculation, CRISPR-mediated RUNX3-knockout HGC-27 cells show suppression of xenograft growth and liver metastasis. We interrogated the potential of RUNX3 as a metastasis driver in gastric cancer by profiling its target genes. Transcriptomic analysis revealed strong involvement of RUNX3 in the regulation of multiple developmental pathways, consistent with the notion that Runt domain transcription factor (RUNX) family genes are master regulators of development. RUNX3 promoted “cell migration” and “extracellular matrix” programs, which are necessary for metastasis. Of note, we found pro-metastatic genes WNT5A, CD44, and VIM among the top differentially expressed genes in RUNX3 knockout versus control cells. Chromatin immunoprecipitation sequencing and HiChIP analyses revealed that RUNX3 bound to the enhancers and promoters of these genes, suggesting that they are under direct transcriptional control by RUNX3. We show that RUNX3 promoted metastasis in part through its upregulation of WNT5A to promote migration, invasion, and anchorage-independent growth in various malignancies. Our study therefore reveals the RUNX3-WNT5A axis as a key targetable mechanism for gastric cancer metastasis.

PMID: 38240752                DOI: 10.1158/2767-9764.CRC-22-0165