Oncofetal protein IGF2BP1 regulates IQGAP3 expression to maintain stem cell potential in cancer
Khine Myint,
Linda Shyue Huey Chuang,
Yu Xuan Teh,
Nur Astiana Mawan,
Edward Jizhong Shi,
Michelle Meng Huang Mok,
Napat Nuttonmanit,
Junichi Matsuo,
Ying Li,
Henry Yang,
Atsushi Okabe,
Atsushi Kaneda,
Motomi Osato,
Jimmy Bok-Yan So,
Wei Peng Yong,
Patrick Tan,
Khay Guan Yeoh,
Yoshiaki Ito
Affiliations
Khine Myint
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Linda Shyue Huey Chuang
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore; Corresponding author
Yu Xuan Teh
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Nur Astiana Mawan
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Edward Jizhong Shi
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Michelle Meng Huang Mok
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Napat Nuttonmanit
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Junichi Matsuo
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Ying Li
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Henry Yang
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Atsushi Okabe
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
Atsushi Kaneda
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
Motomi Osato
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Jimmy Bok-Yan So
Department of Surgery, National University Health System, National University of Singapore, Singapore, Singapore
Wei Peng Yong
Department of Hematology & Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore
Patrick Tan
Duke-NUS Medical School, Singapore, Singapore; Genome Institute of Singapore, Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore
Khay Guan Yeoh
Department of Medicine, National University of Singapore, Singapore, Singapore
Yoshiaki Ito
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore; Corresponding author
Summary: We reported earlier that IQGAP3 is an important stem cell factor in rapidly proliferating isthmus stem cells in the stomach and that IQGAP3 expression is robustly induced in terminally differentiated chief cells and de-differentiated cells following tissue damage. The elevated IQGAP3 expression in cancer and its association with metastasis suggest a fundamental role for IQGAP3 in proliferating cancer stem cells. What causes IQGAP3 upregulation in cancer is unclear. Here, we show that IGF2BP1 and IQGAP3 expression levels are highest in the blastocyst, with both decreasing during adulthood. This suggests that IQGAP3, like IGF2BP1, is an early developmental gene that is aberrantly upregulated upon re-expression of IGF2BP1 during carcinogenesis. IGF2BP1 binds and stabilizes m6A-modified IQGAP3 transcripts. Downstream targets of IGF2BP1, namely SRF and FOXM1, also upregulate IQGAP3 expression. These multiple layers of IQGAP3 regulation, which may safeguard against inappropriate stem cell proliferation, present additional drug targets to inhibit IQGAP3-driven malignant growth.