2. Academic Validation
  3. Inhibition of the transcription factor ZNF281 by SUFU to suppress tumor cell migration

Inhibition of the transcription factor ZNF281 by SUFU to suppress tumor cell migration

  • Cell Death Differ. 2022 Oct 11. doi: 10.1038/s41418-022-01073-1.
Yanran Deng # 1,  Dezhen Peng # 1,  Jing Xiao # 2,  Yunhe Zhao 3,  Wenhao Ding 3,  Shengtao Yuan 1,  Li Sun 1,  Jian Ding 4 5,  Zizhang Zhou 6,  Meixiao Zhan 7
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 210009, Nanjing, China.
  • 2 Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, 519000, Zhuhai, China.
  • 3 State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, 271018, Tai'an, China.
  • 4 Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 210009, Nanjing, China. jding@simm.ac.cn.
  • 5 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China. jding@simm.ac.cn.
  • 6 State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, 271018, Tai'an, China. zhouzz@sdau.edu.cn.
  • 7 Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, 519000, Zhuhai, China. zhanmeixiao1987@163.com.
  • # Contributed equally.
PMID: 36220888 DOI: 10.1038/s41418-022-01073-1
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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