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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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 7

cia-MAF interacts with TIP60 complex.

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cia-MAF interacts with TIP60 complex. (A) Sliver staining of eluate samp...
(A) Sliver staining of eluate sample from RNA pulldown assay, for which Biotin-labeled cia-MAF probes and sphere cell lysate were used. (B) Western blot for the interaction between cia-MAF and P400, TIP60, and RUVBL2. (C) Western blot to detect the enrichment of TIP60 complex in eluate from TRAP assay, for which cia-MAF-MS2 and MCP-GST binding system was used. (D) Split GFP assay to detect the combination of cia-MAF and P400. The GFP signal was shown in bottom right. Scale bars: 10 μm. (E) Colocalization of cia-MAF and P400 in spheres. cia-MAF and P400 were visualized by FISH and immunofluorescence, respectively. The gray values of P400 (red) and cia-MAF (green) signals along the white arrow (left) were in right. Scale bars: 10 μm. (F) Sphere formation (upper) and transwell (lower) assays of primary cells, in which WT cia-MAF, truncate cia-MAF, or mutant cia-MAF were overexpressed. Scale bars: 500 μm (upper panels), 70 μm (lower panels). CD44 FACS (G) and sphere formation (H) of liver cancer cells treated with TH1834 or CB-6644, 2 inhibitors of the TIP60 complex. Scale bars: 500 μm. For all representative images, n = 3 independent experiments performed with similar results.