Abstract
Although the Hedgehog (Hh) pathway plays an evolutionarily conserved role from Drosophila to mammals, some divergences also exist. Loss of Sufu, an important component of the Hh pathway, does not lead to an obvious developmental defect in Drosophila. However, in mammals, loss of SUFU results in serious disorder, even various cancers. This divergence suggests that SUFU plays additional roles in mammalian cells, besides regulating the Hh pathway. Here, we identify that the transcription factor ZNF281 is a novel binding partner of SUFU. Intriguingly, the Drosophila genome does not encode any homologs of ZNF281. SUFU is able to suppress ZNF281-induced tumor cell migration and DNA damage repair by inhibiting ZNF281 activity. Mechanistically, SUFU binds ZNF281 to mask the nuclear localization signal of ZNF281, culminating in ZNF281 cytoplasmic retention. In addition, SUFU also hampers the interactions between ZNF281 and promoters of target genes. Finally, we show that SUFU is able to inhibit ZNF281-induced tumor cell migration using an in vivo model. Taken together, these results uncover a Hh-independent mechanism of SUFU exerting the anti-tumor role, in which SUFU suppresses tumor cell migration through antagonizing ZNF281. Therefore, this study provides a possible explanation for the functional divergence of SUFU in mammals and Drosophila.
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Acknowledgements
We sincerely thank Prof. Lei Xue (Tongji University, China) for providing scrib-RNAi fly and Prof. Yong Li (Nanchang University, China) for providing lentiviral vectors.
Funding
This work was supported by grants from the National Natural Science Foundation of China (31922011, 31802012, and ZR2021MH137), the National Key Research and Development Program of China (2017YFA0205200), Program for Scientific Research Innovation Team of Young Scholar in Colleges and Universities of Shandong Province (2019KJE009), and the Construction Engineering Special Fund of “Taishan Scholars” (no. Ts201712022).
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MZ, ZZ, and JD designed this study and provide financial support. YD, DP, JX, YZ, WD, SY, and LS carried out the experiments and analyzed the data. SY and LS provided HCC cell lines. YD and DP performed mouse experiments. YZ analyzed cell migration in Drosophila. YD and ZZ wrote the article with the assistance of all authors. MZ, ZZ, and JD supervised this study and modified the manuscript. All authors read and approved the final paper.
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Deng, Y., Peng, D., Xiao, J. et al. Inhibition of the transcription factor ZNF281 by SUFU to suppress tumor cell migration. Cell Death Differ 30, 702–715 (2023). https://doi.org/10.1038/s41418-022-01073-1
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DOI: https://doi.org/10.1038/s41418-022-01073-1
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