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

doi:10.1016/j.isci.2022.105194

Oncofetal protein IGF2BP1 regulates IQGAP3 expression to maintain stem cell potential in cancer

iScience. 2022 Sep 23;25(10):105194. doi: 10.1016/j.isci.2022.105194. eCollection 2022 Oct 21.

Authors

Khine Myint¹, Linda Shyue Huey Chuang¹, Yu Xuan Teh¹, Nur Astiana Mawan¹, Edward Jizhong Shi¹, Michelle Meng Huang Mok¹, Napat Nuttonmanit¹, Junichi Matsuo¹, Ying Li¹, Henry Yang¹, Atsushi Okabe², Atsushi Kaneda², Motomi Osato¹, Jimmy Bok-Yan So³, Wei Peng Yong⁴, Patrick Tan^{5

6

1}, Khay Guan Yeoh⁷, Yoshiaki Ito¹

Affiliations

¹ Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive #12-01, Singapore 117599, Singapore.
² Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
³ Department of Surgery, National University Health System, National University of Singapore, Singapore, Singapore.
⁴ Department of Hematology & Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.
⁵ Duke-NUS Medical School, Singapore, Singapore.
⁶ Genome Institute of Singapore, Singapore, Singapore.
⁷ Department of Medicine, National University of Singapore, Singapore, Singapore.

Abstract

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.

Keywords: Cell biology; cancer; stem cells research.