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Zinc-finger protein 545 is a novel tumour suppressor that acts by inhibiting ribosomal RNA transcription in gastric cancer
  1. Shiyan Wang1,
  2. Yingduan Cheng2,
  3. Wan Du1,3,
  4. Leina Lu4,
  5. Liang Zhou5,
  6. Huating Wang5,
  7. Wei Kang6,
  8. Xiaoxing Li1,
  9. Qian Tao2,
  10. Joseph J Y Sung1,
  11. Jun Yu1
  1. 1Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Hong Kong, Hong Kong
  2. 2Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  3. 3GI Division, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai Institution of Digestive Disease, Shanghai, China
  4. 4Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  5. 5Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  6. 6Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  1. Correspondence to Dr Professor Jun Yu, Institute of Digestive Disease and Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong; junyu{at}cuhk.edu.hkProfessor Qian Tao, Department of Clinical Oncology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong; qtao{at}clo.cuhk.edu.hk

Abstract

Objective Zinc-finger protein 545 (ZNF545) is a member of the family of Krüppel-associated box-containing zinc-finger proteins. The aim of this study was to clarify its biological function as a tumour suppressor in gastric cancer.

Design The biological function of ZNF545 was determined by cell growth and apoptosis assays. The ZNF545 target signal pathway was identified by promoter luciferase assay, northern blot, run-on transcription assay, chromatin immunoprecipitation and coimmunoprecipitation assays. The clinical application of ZNF545 was assessed in primary gastric cancers.

Results ZNF545 was silenced or reduced in 16 out of 18 gastric cancer cell lines by promoter hypermethylation. Restoration of ZNF545 expression in gastric cancer cell lines suppressed cell proliferation and induced apoptosis. These effects of ZNF545 were attributed to inhibition of ribosomal RNA (rRNA) transcription. Inhibition of rRNA transcription by ZNF545 was further revealed to be associated with direct ribosomal DNA (rDNA) promoter binding, recruitment of the corepressor, heterochromatin protein 1β, and reduction of trimethylated histone H3 at the Lys4 residue at the rDNA locus. ZNF545 methylation was detected in 51.9% (41/79) of gastric cancer tissues, 27.0% (20/74) of adjacent non-tumour gastric tissues (p=0.001), but none of 20 normal controls. Multivariate analysis revealed that patients with ZNF545 methylation had a significant decrease in overall survival. Kaplan–Meier survival curves showed that ZNF545 methylation was significantly associated with shortened survival in patients with stage I–II gastric cancer.

Conclusions ZNF545 acts as a functional tumour suppressor in gastric cancer by inhibiting rRNA transcription. Its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.

  • Zinc finger protein 545
  • tumour suppressor
  • rRNA transcription
  • gastric cancer
  • prognosis
  • cancer
  • tumour markers
  • methylation
  • gene regulation
  • molecular carcinogenesis
  • molecular oncology
  • colorectal adenomas
  • gastrointestinal bleeding
  • colorectal cancer screening
  • non-alcoholic steatohepatitis

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Footnotes

  • Funding This project was supported by National Basic Research Program of China (973 Program, 2010CB529305); Research Grants Council RGC CERG CUHK (473008); Group Research Scheme CUHK (3110043); CUHK Focused Investment Gant (1903026), and RFCID (10090942, 11100022).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Clinical Research Ethics Committee of the Chinese University of Hong Kong.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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