LINC01021 maintains tumorigenicity by enhancing N6-methyladenosine reader IMP2 dependent stabilization of MSX1 and JARID2: implication in colorectal cancer.

Abstract

Insulin-like growth factor-2 mRNA-binding protein 2 (IGF2BP2, also known as IMP2), a novel class III N6-methyladenosine (m6A) reader, has recently gained attention due to its critical functions in recognizing and stabilizing m6A modified oncogenic transcripts. However, whether and how long non-coding RNAs (lncRNAs) facilitate IMP2's role as m6A "reader" remains elusive, particularly in colorectal cancer (CRC). Here, we demonstrated that oncogenic LINC021 specifically bound with the m6A "reader" IMP2 protein and enhanced the mRNA stability of MSX1 and JARID2 in an m6A regulatory manner during CRC tumorigenesis and pathogenesis. Specifically, a remarkable upregulation of LINC021 was confirmed in CRC cell lines and clinical tissues (n = 130). High level of LINC021acted as an independent prognostic predictor for CRC clinical outcomes. Functional assays demonstrated that LINC021 exerted its functions as an oncogene to aggravate CRC malignant phenotypes including enhanced cell proliferation, colony formation, migration capabilities, and reduced cell apoptosis. Mechanistically, LINC021 directly recognized IMP2 protein, the latter enhanced the mRNA stability of transcripts such as MSX1 and JARID2 by recognizing their m6A-modified element RGGAC. Thus, these findings uncovered an essential LINC021/IMP2/MSX1 and JARID2 signaling axis in CRC tumorigenesis, which provided profound insights into our understanding of m6A modification regulated by lncRNA in CRC initiation and progression and shed light on the targeting of this axis for CRC treatment.

• Authors: Huizhe Wu, Xiangyu Ding, Xiaoyun Hu, Qing Zhao, Qiuchen Chen, Tong Sun, Yalun Li, Hao Guo, Meng Li, Ziming Gao, Weifan Yao, Lin Zhao, Kai Li, Minjie Wei
• Journal: Oncogene (Oncogene) Vol. 41 Issue 13 Pg. 1959-1973 (03 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35173309 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• IGF2BP2 protein, human
• JARID2 protein, human
• MSX1 Transcription Factor
• MSX1 protein, human
• RNA, Long Noncoding
• RNA-Binding Proteins
• N-methyladenosine
• Polycomb Repressive Complex 2
• Adenosine

Topics

• Adenosine (analogs & derivatives, metabolism)
• Carcinogenesis (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Colorectal Neoplasms (pathology)
• Gene Expression Regulation, Neoplastic
• Humans
• MSX1 Transcription Factor (genetics, metabolism)
• Polycomb Repressive Complex 2 (genetics)
• RNA, Long Noncoding (genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)