N⁶-methyladenosine (m⁶A) reader IGF2BP1 facilitates clear-cell renal cell carcinoma aerobic glycolysis

Abstract

Emerging articles have reported that N6-methyladenosine (m6A) modification is mainly involved in clear-cell renal cell carcinoma (ccRCC) tumorigenesis. However, the regulatory mechanisms of m6A reader IGF2BP1 involved in ccRCC tumor energy metabolism are currently unknown. Results showed that the m6A reader IGF2BP1 exhibited significantly higher expression in ccRCC cells. Functionally, results by gain/loss functional assays indicated that IGF2BP1 promoted the glycolytic characteristics, including glucose uptake, lactate production and extracellular acidification rate (ECAR). Mechanistically, IGF2BP1 recognized the m6A modified sites on LDHA mRNA and enhanced its mRNA stability, thereby accelerating tumor energy metabolism. Thus, our work reveals a novel facet of the m6A that promoted mRNA stability and highlighted the functional importance of IGF2BP1 as m6A readers in post-transcriptional gene regulation.

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

“… 264 The gain/loss functional assays proved IGF2BP1-mediated stabilization of LDHA mRNA in ccRCC. 265 Moreover, upregulated IGF2BP2 has been found as a predictor of poor prognosis in CC and OSCC, which improved stability of c-MYC and HK2 mRNA, respectively. 266 , 267 Recently, Ye et al suggested that miR4458HG interacted with IGF2BP2 and activated the improvement of HK2 and GLUT1 expression in HCC.…”

The role of RNA-modifying proteins in renal cell carcinoma

“…IGF2BPs, in turn, enhance the stability of the S1PR3 mRNA [ 53 ]. IGF2BP1 was upregulated in ccRCC cell lines and facilitated tumor energy metabolism by promoting glycolysis [ 77 ]. Moreover, the upregulation of IGF2BP3 activated the nuclear factor kappa B (NF-кB) pathway, which promoted RCC cell migration and invasion [ 78 ].…”

m6A-regulated tumor glycolysis: new advances in epigenetics and metabolism

“…After that, PDK4 and IGF2BP3 combine to obtain stronger stability, or combine with YTHDF1/eEF-2 complex to improve translation efficiency Promote glycolysis and proliferation of cancer cells [ 147 ] IGF2BP2 E6/E7 protein produced by HPV can promote the expression of IGF2BP2, make it recognize and bind more m6A-MYC mRNA Promote the proliferation and glycolysis of cervical cancer cells [ 149 ] Renal carcinoma METTL14 The transcription factor BPTF can enhance the glycolysis of cancer cells to drive the distant metastasis of renal cell carcinoma. However, this process is inhibited by METTL14 Inhibit the glycolysis and the distant metastasis of renal cell carcinoma [ 150 ] METTL3 MTHFD2 has a positive regulatory effect on METTL3-induced HIF-2α mRNA methylation Promote the glycolysis and proliferation of cancer cells [ 151 ] IGF2BP1 IGF2BP1 directly binds to the m6A modification site on LDHA mRNA, thereby enhancing the stability of LDHA mRNA Promoting glycolysis and malignant phenotype of renal cell carcinoma [ 152 ] Osteosarcoma RBM15 Circ-CTNNB1 directly combines with RBM15 to increase the expression of glycolytic enzyme in an m6A-dependent manner Promote glycolysis and development of osteosarcoma [ 153 ] YTHDF3 The stability of m6A-modified PGK1 mRNA was improved after binding to YTHDF3 Promote glycolysis and proliferation of osteosarcoma cells [ 154 ] Oral squamous cell carcinoma IGF2BP3 m6A-circFOXK2 and IGF2BP3 act synergistically on GLUT1 mRNA to improve its stability Promote glycolysis and transfer of OSSC [ 156 ] Glioblas...…”