Abstract

IGF2BP1, an m 6 A reader, plays important roles in the tumorigenesis and self-renewal of cancer stem cells (CSCs). However, the ability of IGF2BP1 to recognize m 6 A-modified RNA has not been fully demonstrated. Here, we found that the E3 ubiquitin ligase FBXO28 mediated the K63-conjugated ubiquitination of IGF2BP1 at the K560 site. This ubiquitination strengthened the association of IGF2BP1 with a subset of m 6 A-modified RNAs and subsequently promoted the stability of the mRNAs that are targeted by IGF2BP1. Additionally, FBXO28 was upregulated in CSCs and promoted the stemness of various types of cancer cells. The crucial CSC-regulating gene KIT was identified as a direct target of IGF2BP1 that mediated the ability of FBXO28 to promote the stemness of cancer cells, and the protein level of KIT was positively correlated with FBXO28 levels in cancer patients. More importantly, the suppression of FBXO28/IGF2BP1 via siRNA or an inhibitor sensitized CSCs to the killing effect of a KIT inhibitor. Our results revealed a novel regulatory mechanism underlying m 6 A-modified RNA recognition by IGF2BP1 and highlighted the clinical significance of the FBXO28/IGF2BP1/KIT signaling axis in eradicating cancer.