N6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis

Abstract

Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N6-methyladenosine (m6A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N6-methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N6-methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease.

m6A-binding proteins: the emerging crucial performers in epigenetics

“…Moreover, circNSUN2 is a circular RNA that facilitates CRC cells metastasis and aggressiveness, and contains m 6 A methylation at the exon 5-exon 4 junction site [51]. On the one hand, YTHDC1 promoted circNSUN2 export from nucleus to cytoplasm.…”

“…On the one hand, YTHDC1 promoted circNSUN2 export from nucleus to cytoplasm. On the other hand, the KH3-4 di-domain of IGF2BP2 interacted with cir-cNSUN2 and then form a circNSUN2/IGF2BP2 complex to fortify the stability of HMGA2 that was a RNA inducing EMT and promoting CRC liver metastasis [51]. In addition, SOX2, an important gene to promote tumor initiation and metastasis, exhibited an elevated m 6 A level [52].…”

“…Increasing the expression of β-catenin, WNT6 and FZD9A to activate Wnt/β-catenin pathway [49] YTHDF3 GAS5 Enhancing the degradation of lncRNA GAS5 [50] YTHDC1 circNSUN2 Facilitating circNSUN2 export from nucleus to cytoplasm [51] IGF2BP2 HMGA2 Forming a circNSUN2/IGF2BP2 complex to fortify the stability of HMGA2 [51] IGF2BP2 SOX2 Stabilizing SOX2 mRNA [52] Gastric cancer IGF2BP1 SEC62 Augmenting SEC62 mRNA translation [53] IGF2BP3 HDGF Facilitating HDGF mRNA expression [54] HuR ZMYM1 Fortifying the stability of ZMYM1 mRNA [116] Lung cancer YTHDF1 CDK2, CDK4, cyclinD1…”

Functions and clinical significance of circular RNAs in glioma

“…Park et al revealed that m6A recognized the binding of the protein YTHDF2 to the target molecule and recruited HRSP12 to mediate the cleavage of circRNA by the RNA endonuclease RNase P/MRP complex, suggesting critical significances to perceive circRNAs dynamic change [152]. Also, a new study from Chen et al demonstrated that the nuclear export of circNSUN2 is mediated by YTHDC1 in an m6A methylation-dependent manner [153]. All data highlights the significance of epigenetic alterations regulating the biogenesis and metabolism of circRNAs.…”

N6-Methyladenosine: A Novel RNA Imprint in Human Cancer

“…Furthermore, IGF2BP2 has recently been proven to mediate colorectal liver metastasis, testified both in vitro and in vivo with metastasis PDX models (72). Mechanistically, the m 6 A modification of circNSUN2 is recognized by YTHDC1, which accelerates the cytoplasmic export and further stabilizes HMGA2 mRNA by forming a circNSUN2/IGF2BP2/HMGA2 ternary complex in the cytoplasm.…”