rtcisE2F promotes the self-renewal and metastasis of liver tumor-initiating cells via N6-methyladenosine-dependent E2F3/E2F6 mRNA stability.

Abstract

Liver cancer is highly heterogeneous, and the tumor tissue harbors a variety of cell types. Liver tumor initiating cells (TICs) well contribute to tumor heterogeneity and account for tumor initiation and metastasis, but the molecular mechanisms of liver TIC self-renewal are elusive. Here, we identified a functional read-through rt-circRNA, termed rtcisE2F, that is highly expressed in liver cancer and liver TICs. rtcisE2F plays essential roles in the self-renewal and activities of liver TICs. rtcisE2F targets E2F6 and E2F3 mRNAs, attenuates mRNA turnover, and increases E2F6/E2F3 expression. Mechanistically, rtcisE2F functions as a scaffold of N-methyladenosine (m6A) reader IGF2BP2 and E2F6/E2F3 mRNA. rtcisE2F promotes the association of E2F6/E2F3 mRNAs with IGF2BP2, and inhibits their association with another m6A reader, YTHDF2. IGF2BP2 inhibits E2F6/E2F3 mRNA decay, whereas YTHDF2 promotes E2F6/E2F3 mRNA decay. By switching m6A readers, rtcisE2F enhances E2F6/E2F3 mRNA stability. E2F6 and E2F3 are both required for liver TIC self-renewal and Wnt/β-catenin activation, and inhibition of these pathways is a potential strategy for preventing liver tumorigenesis and metastasis. In conclusion, the rtcisE2F-IGF2BP2/YTHDF2-E2F6/E2F3-Wnt/β-catenin axis drives liver TIC self-renewal and initiates liver tumorigenesis and metastasis, and may provide a strategy to eliminate liver TICs.

• Authors: Zhenzhen Chen, Lan Huang, Kaili Wang, Lulu Zhang, Xiang Zhong, Zhongyi Yan, Benyu Liu, Pingping Zhu
• Journal: Science China. Life sciences (Sci China Life Sci) Vol. 65 Issue 9 Pg. 1840-1854 (09 2022) ISSN: 1869-1889 [Electronic] China
• PMID: 35266112 (Publication Type: Journal Article)
• Copyright: © 2022. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• E2F3 Transcription Factor
• E2F3 protein, human
• E2F6 Transcription Factor
• E2F6 protein, human
• IGF2BP2 protein, human
• RNA, Long Noncoding
• RNA, Messenger
• RNA-Binding Proteins
• Transcription Factors
• beta Catenin
• N-methyladenosine
• Adenosine

Topics

• Adenosine (analogs & derivatives)
• Carcinogenesis (metabolism)
• Cell Line, Tumor
• E2F3 Transcription Factor
• E2F6 Transcription Factor (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms (metabolism)
• Neoplastic Stem Cells (metabolism)
• RNA Stability
• RNA, Long Noncoding (genetics)
• RNA, Messenger (genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Transcription Factors (metabolism)
• beta Catenin (genetics, metabolism)