A Novel 19q13 Nucleolar Zinc Finger Protein Suppresses Tumor Cell Growth through Inhibiting Ribosome Biogenesis and Inducing Apoptosis but Is Frequently Silenced in Multiple Carcinomas

Zhaohui Wang,Jianming Ying,Margaret H.L Ng,Qian Tao,Yingduan Cheng,Pei Liang,Hua Geng,Anthony T.C Chan,Suk Hang Cheng,Lili Li,Tony S.K Mok,Ka Man Ng,Xianwei Su

doi:10.1158/1541-7786.mcr-11-0594

Abstract

Epigenetic disruption of tumor suppressor genes is frequently involved in tumorigenesis. We identified a novel 19q13 KRAB domain-containing zinc finger protein, ZNF545/ZFP82, broadly expressed in normal tissues but downregulated in multiple tumor cell lines. The ZNF545 promoter contains a CpG island, which is frequently methylated in cell lines. The transcriptional silencing of ZNF545 could be reversed by pharmacologic or genetic demethylation, indicating direct epigenetic silencing. ZNF545 was also frequently methylated in multiple primary tumors of nasopharyngeal, esophageal, lung, gastric, colon, and breast, but rarely in normal epithelial tissues and paired normal tissues. ZNF545 is located in the nucleus and mainly sequestered in nucleoli, functioning as a repressor. ZNF545 is able to repress NF-κB and AP-1 signaling pathways, whereas ectopic expression of ZNF545 in silenced tumor cells significantly inhibited their growth and induced apoptosis. Functional studies showed that ZNF545 was involved in ribosome biogenesis through inhibiting the activity of rDNA promoter and decreasing cellular protein translation efficiency. Thus, we identified ZNF545 as a novel tumor suppressor inducing tumor cell apoptosis, repressing ribosome biogenesis and target gene transcription. The tumor-specific methylation of ZNF545 could be an epigenetic biomarker for cancer diagnosis.

Highlights

Zinc finger proteins (ZFP) are common transcription factors in all eukaryotes as the largest transcription factor family in mammals
Through massive expression profiling of 19q13 ZFPs in normal and tumor cell lines, we identified a novel KRAB-ZFP protein, ZNF545, as one of the downregulated genes in carcinoma cell lines
ZNF545 was highly expressed in 9 immortalized epithelial cell lines (NP69, NE1, NE3, Het-1A, NE083, CCD 841-CoN, HMEC, HMEpC, and RHEK1) but frequently silenced or reduced in multiple carcinoma cell lines including nasopharyngeal carcinoma (NPC), esophageal squamous cell carcinoma (ESCC), gastric, colon carcinomas, infrequently downregulated ZNF545 was observed in hepatocellular, lung, breast, renal, prostate, and cervical cancer cell lines (Fig. 1C, Supplementary Fig. S1)

Summary

Introduction

Zinc finger proteins (ZFP) are common transcription factors in all eukaryotes as the largest transcription factor family in mammals. ZFPs bind to promoters with their zinc finger domains and activate or repress gene expression through their association proteins [1, 6]. About one-third of the ZFPs are Kru€ppel-associated box containing zinc finger proteins (KRAB-ZFP). Many KRAB-ZFPs are Authors' Affiliations: 1Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute; 2Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong; 3Shenzhen Institute of Advanced Technology, Chinese Academy of Science-CUHK, Shenzhen; and 4Department of Pathology, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.

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