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 language | English |
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Pages (from-to) | 6590-6600 |
Number of pages | 11 |
Journal | Oncogene |
Volume | 40 |
Issue number | 48 |
DOIs | |
State | Published - Dec 2 2021 |
Bibliographical note
Publisher Copyright:© 2021, The Author(s).
Funding
This study was supported by National Key R&D Program of China (No. 2020YFA0509200/ 2020YFA0509203); RGC-CRF Hong Kong (C4039-19G, C7065-18GF); RGC-GRF Hong Kong (14163817, 14110819); Vice-Chancellor’s Discretionary Fund CUHK.
Funders | Funder number |
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RGC-CRF | C4039-19G, C7065-18GF |
RGC-GRF Hong Kong | 14110819, 14163817 |
National Key Basic Research and Development Program of China | 2020YFA0509200/ 2020YFA0509203 |
National Key Basic Research and Development Program of China |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research