circRARS synergises with IGF2BP3 to regulate RNA methylation recognition to promote tumour progression in renal cell carcinoma

Yuenan Liu; Kailei Chen; Yi Shou; Sen Li; Jun Wang; Qingyang Zhang; Ziwei Huang; Jiaju Xu; Mingfeng Li; Di Liu; Huageng Liang; Hongmei Yang; Xiaoping Zhang

doi:10.1002/ctm2.1512

circRARS synergises with IGF2BP3 to regulate RNA methylation recognition to promote tumour progression in renal cell carcinoma

Clin Transl Med. 2023 Dec;13(12):e1512. doi: 10.1002/ctm2.1512.

Authors

Yuenan Liu^{1

2}, Kailei Chen^{1

2}, Yi Shou^{1

2

3}, Sen Li^{1

2}, Jun Wang^{1

2}, Qingyang Zhang⁴, Ziwei Huang⁵, Jiaju Xu^{1

2}, Mingfeng Li^{1

2}, Di Liu^{1

2}, Huageng Liang^{1

2}, Hongmei Yang⁶, Xiaoping Zhang^{1

2

7}

Affiliations

¹ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
² Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
³ Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.
⁴ Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
⁵ Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
⁶ Department of Pathogenic Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, P. R. China.
⁷ Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, P. R. China.

Abstract

As the most prominent RNA modification, N6-methyladenosine (m⁶ A) participates in the regulation of tumour initiation and progression. Circular RNAs (circRNAs) also play crucial roles in ubiquitous life processes. Whether circRNAs are required for m⁶ A regulation in renal cell carcinoma (RCC) remains unclear. Meta-analysis and bioinformatics identified that IGF2BP3 was upregulated in RCC and indicated a worse prognosis. IGF2BP3 significantly promoted RCC progression in vitro and in vivo. Mechanistically, circRARS bound to KH1-KH2 domains of IGF2BP3 to enhance m⁶ A modification recognition. A 12-nt sequence (GUCUUCCAGCAA) was proven to be the IGF2BP3-binding site of circRARS. Additionally, CAPN15, CD44, HMGA2, TNRC6A and ZMIZ2 were screened to be the target genes regulated by the IGF2BP3/circRARS complex in an m⁶ A-dependent manner. Stabiliser proteins, including HuR, Matrin3 and pAbPC1, were recruited by circRARS, thereby increasing the mRNA stability of the forementioned five target genes. Consequently, the IGF2BP3/circRARS complex facilitated the lipid accumulation of RCC cells and promoted sunitinib resistance via target genes. circRARS synergised with IGF2BP3 to facilitate m⁶ A recognition, thereby promoting RCC progression. Thus, IGF2BP3 could be a potential biomarker for RCC diagnosis and prognosis and a therapeutic target.

Keywords: IGF2BP3; circRARS; m6A methylation; renal cell carcinoma; tumour progression.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Calpain
Carcinoma, Renal Cell* / genetics
Cell Transformation, Neoplastic
Humans
Kidney Neoplasms* / genetics
Protein Inhibitors of Activated STAT
RNA Methylation
RNA, Circular / genetics

Substances

Calpain
CAPN15 protein, human
Protein Inhibitors of Activated STAT
RNA, Circular
ZMIZ2 protein, human
IGF2BP3 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding