Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF
Zhenzhen Chen, … , Zusen Fan, Pingping Zhu
Zhenzhen Chen, … , Zusen Fan, Pingping Zhu
Published August 17, 2021
Citation Information: J Clin Invest. 2021;131(19):e148020. https://doi.org/10.1172/JCI148020.
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Research Article Cell biology Oncology

Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF

Abstract

Liver tumor-initiating cells (TICs) are involved in liver tumorigenesis, metastasis, drug resistance, and relapse, but the regulatory mechanisms of liver TICs are largely unknown. Here, we have identified a functional circular RNA, termed circRNA activating MAFF (cia-MAF), that is robustly expressed in liver cancer and liver TICs. cia-MAF–KO primary cells and cia-maf–KO liver tumors harbor decreased ratios of TICs, and display impaired liver tumorigenesis, self-renewal, and metastatic capacities. In contrast, cia-MAF overexpression drives liver TIC propagation, self-renewal, and metastasis. Mechanistically, cia-MAF binds to the MAFF promoter, recruits the TIP60 complex to the MAFF promoter, and finally promotes MAFF expression. Loss of cia-MAF function attenuates the combination between the TIP60 complex and the MAFF promoter. MAFF is highly expressed in liver tumors and liver TICs, and its antisense oligo (ASO) has therapeutic potential in treating liver cancer without MAFA/MAFG gene copy number alterations (CNAs). This study reveals an additional layer for liver TIC regulation as well as circRNA function, and provides an additional target for eliminating liver TICs, especially for liver tumors without MAFA/MAFG gene CNAs.

Authors

Zhenzhen Chen, Tiankun Lu, Lan Huang, Zhiwei Wang, Zhongyi Yan, Yubo Guan, Wenjing Hu, Zusen Fan, Pingping Zhu

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Figure 8

cia-MAF recruits the TIP60 complex to the MAFF promoter.

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cia-MAF recruits the TIP60 complex to the MAFF promoter. (A) Real-time P...
(A) Real-time PCR to detect the enrichment of MAFF promoter in eluate from ChIP assay, for which P400, TIP60, and RUVBL2 antibodies and cia-MAF–KO spheres were used. n = 3 independent experiments. (B) Colocalization of MAFF promoter and TIP60 components (P400, TIP60, and RUVBL2) in cia-MAF–KO and control cells. n = 6 independent experiments. Western blot to detect P400 in eluate from CAPTURE assay, for which cia-maf–KO sphere (C) or cia-MAF–KO spheres (D) were used. For C, WT littermates were used as controls. (E) Western blot for P400 in eluate from CAPTURE assay using cia-MAF–overexpressing and control spheres. (F) Western blot for MAFF detection upon cia-MAF overexpression, which was performed in MAFF promoter knockout cells. (G and H) CD44 FACS and sphere formation upon cia-MAF overexpression, which were generated in WT and MAFF-P–KO cells. n = 3 independent experiments. In all panels, data are shown as mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001. Significance was determined by 1-way ANOVA (A, B, and D) or 1-tailed Student’s t test (E, F, and H). For D–F, typical images are in the left panel and signal intensities quantified with Image J are in the right panel. For all representative images, n= 3 independent experiments performed with similar results.