RNA m6A reader IGF2BP3 promotes metastasis of triple‐negative breast cancer via SLIT2 repression

Abstract

Triple-negative breast cancer (TNBC) is a group of fatal malignancies characterized by high metastatic capacity, the underlying mechanisms of which remain largely elusive. We have found here that insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is highly expressed in TNBC and correlates clinically with distant metastasis-free survival of TNBC patients. IGF2BP3 promotes the migration and invasion capabilities of TNBC cells dependent upon cellular RNA N6-methyladenosine (m6A) modification. Mechanistically, IGF2BP3 binds to and destabilizes m6A-methylated mRNA of the extracellular matrix glycoprotein, SLIT2, impairs its downstream signaling via the cognate receptor ROBO1, and consequently triggers the activation of canonical PI3K/AKT and MEK/ERK pathways. The IGF2BP3/SLIT2 axis is critically involved in the regulation of TNBC metastasis in vivo. These findings shed light into the regulatory network of distant metastasis of breast cancer and provide rationale for targeting the m6A machinery in the treatment of TNBC.

Association of the m6A reader IGF2BP3 with tumor progression and brain‐specific metastasis in breast cancer

“…IGF2BP3 binds to and destabilizes SLIT2 m 6 A-methylated mRNA, consequently triggering the activation of canonical PI3K/AKT pathway. 45 Samanta et al 24 demonstrated that knockout of IGF2BP3 expression improved the chemosensitivity of TNBC to doxorubicin and mitoxantrone. This enhancement is attributable to the ability of IGF2BP3…”

“…As an m 6 A reader protein, IGF2BP3 can recognize and bind to mRNA transcripts targets via the m 6 A motif and regulate mRNA stabilization and translation. IGF2BP3 binds to and destabilizes SLIT2 m 6 A‐methylated mRNA, consequently triggering the activation of canonical PI3K/AKT pathway 45 . Samanta et al 24 .…”

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

“…m6A-binding proteins bind to the m6A methylation site. They include YT521-B homology (YTH) domain family proteins (YTHDFs), YTH domain-containing protein (YTHDCs) [ 54 ], insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BPs) [ 55 ], eIF3 [ 46 , 56 , 57 , 58 ], and heterogeneous nuclear ribonucleoproteins (HNRNPs) [ 59 ]. IGF2BP2 enhances renal cell carcinoma tumorigenesis by stabilizing sphingosine-1-phosphate receptor 3 (S1PR3) mRNA [ 60 ].…”

“…m6A regulators, such as m6A-binding proteins, can play roles in cancer initiation and progression. IGF2BP3 promoted the migration and invasion of triple negative breast cancer (TNBC) cells in an m6A modification-dependent manner [ 55 ]. IGF2BP3 bound to and destabilized the m6A-methylated mRNA of the extracellular matrix glycoprotein, slit guidance ligand 2 (SLIT2), to decrease the expression of SLIT and enhances the metastatic potential of TNBCs [ 55 ].…”

“…IGF2BP3 promoted the migration and invasion of triple negative breast cancer (TNBC) cells in an m6A modification-dependent manner [ 55 ]. IGF2BP3 bound to and destabilized the m6A-methylated mRNA of the extracellular matrix glycoprotein, slit guidance ligand 2 (SLIT2), to decrease the expression of SLIT and enhances the metastatic potential of TNBCs [ 55 ]. In doing so, IGF2BP3 activated canonical PI3K/AKT and MEK/ERK pathways [ 55 ].…”