ZNF545 loss promotes ribosome biogenesis and protein translation to initiate colorectal tumorigenesis in mice

Shiyan Wang, Chi Chun Wong, Yanquan Zhang, Junzhe Huang, Chuangen Li, Jianning Zhai, Guoping Wang, Hong Wei, Xueji Zhang, Housheng Hansen He, Jun Yu

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Ribosome biogenesis plays a pivotal role in tumorigenesis by supporting robust protein translation. We investigate the functional and molecular mechanism of Zinc finger protein 545 (ZNF545), a transcriptional repressor for ribosomal RNA (rRNA), in colorectal cancer (CRC). ZNF545 was silenced in CRC compared to adjacent normal tissues (P < 0.0001), implying a tumor-suppressive role. Colon-specific Znf545 knockout in mice accelerated CRC in ApcMin/+ and azoxymethane/dextran sulfate sodium-induced CRC. Mechanistically, we demonstrated that ZNF545 uses its two zinc finger clusters to bind to minimal rDNA promoter, where it assembled transcriptional repressor complex by interacting with KAP1. Znf545 deletion in mouse embryonic fibroblasts not only increased rRNA transcription rate and the nucleolar size and number but also altered the nucleolar composition and architecture with an increased number of fibrillar centers surrounded by net-like dense fibrillar components. Consequently, Znf545 deletion promoted the gene expression of translation machinery, protein translation, and cell growth. Consistent with its tumor-suppressive role, ZNF545 overexpression in CRC cells induced growth arrest and apoptosis. Finally, administration of rRNA synthesis inhibitor, CX-5461, inhibited CRC development in Znf545Δ/ΔApcMin/+ mice. In conclusion, ZNF545 suppresses CRC through repressing rRNA transcription and protein translation. Targeting rRNA biosynthesis in ZNF545-silenced tumors is a potential therapeutic strategy for CRC.

Original languageEnglish
Pages (from-to)6590-6600
Number of pages11
JournalOncogene
Volume40
Issue number48
DOIs
StatePublished - Dec 2 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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