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ZNF677 Suppresses Akt Phosphorylation and Tumorigenesis in Thyroid Cancer Yujun Li1, Qi Yang1, Haixia Guan2, Bingyin Shi1,3, Meiju Ji4, and Peng Hou1,3

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ZNF677 Suppresses Akt Phosphorylation and Tumorigenesis in Thyroid Cancer Yujun Li1, Qi Yang1, Haixia Guan2, Bingyin Shi1,3, Meiju Ji4, and Peng Hou1,3 Published OnlineFirst July 11, 2018; DOI: 10.1158/0008-5472.CAN-18-0003 Cancer Molecular Cell Biology Research ZNF677 Suppresses Akt Phosphorylation and Tumorigenesis in Thyroid Cancer Yujun Li1, Qi Yang1, Haixia Guan2, Bingyin Shi1,3, Meiju Ji4, and Peng Hou1,3 Abstract The zinc finger protein 677 (ZNF677) belongs to the zinc apoptosis. Conversely, knockdown of ZNF677 promoted thy- finger protein family, which possesses transcription factor roid cancer cell proliferation and colony formation. ZNF677 activity by binding sequence-specific DNA. Previous studies exerted its tumor suppressor functions in thyroid cancer cells have reported its downregulated by promoter methylation in through transcriptional repression of two targets CDKN3 and non–small cell lung cancer. However, its biological role and HSPB1 (or HSP27), thereby inhibiting phosphorylation and exact mechanism in human cancers, including thyroid cancer, activation of Akt via distinct mechanisms. Taken together, our remain unknown. In this study, we demonstrate that ZNF677 data show that ZNF677 functions as a tumor suppressor and is frequently downregulated by promoter methylation in is frequently silenced via promoter methylation in thyroid primary papillary thyroid cancers (PTC) and show that cancer. decreased expression of ZNF677 is significantly associated with poor patient survival. Ectopic expression of ZNF677 in Significance: These findings report a tumor suppressive thyroid cancer cells dramatically inhibited cell proliferation, role of the zinc-finger protein ZNF677 in primary papillary colony formation, migration, invasion, and tumorigenic thyroid cancer through inhibition of Akt phosphorylation. potential in nude mice and induced cell-cycle arrest and Cancer Res; 78(18); 5216–28. Ó2018 AACR. Introduction compelling need for developing additional therapeutic targets and treatment options. The incidence of thyroid cancer has increased rapidly in recent An increasing body of evidence suggests that epigenetic years, especially in women, and has become one of the highest in changes such as DNA methylation, remodeling, and posttrans- the world including China (1, 2). Generally, the majority of the lational modification of chromatin play critical roles in thyroid patients with well-differentiated thyroid cancer (WDTC) have an tumorigenesis, as a result of their effects on tumor cell differ- excellent prognosis and can be efficiently cured by conventional entiation, proliferation, and survival (4–6). Of these epigenetic therapies (surgery with or without radioiodinated therapy and alterations, promoter methylation is widely investigated in suppression therapy with thyroid hormone); however, some human cancers and considered as one of the major mechanisms patients can develop advanced disease such as metastatic differ- to inactivate tumor suppressor genes (7, 8). So far, many genes entiated thyroid cancer (DTC), poorly differentiated thyroid have been identified to be transcriptionally inactivated by cancer (PDTC), and anaplastic thyroid cancer (ATC) that fail to promoter methylation in different types of cancer including respond to conventional therapies, resulting in morbidity and thyroid cancer (9). Zinc finger proteins are the largest tran- mortality (3). The mechanisms underlying dedifferentiation of scription factor family in human genome, which have a wide thyroid cancer are incompletely understood. Thus, there is a variety of functions in human diseases including cancers through transcriptionally activating or repressing their targets (10). The majority of zinc finger proteins contain Kruppel€ associated box (KRAB) domains, which has been demonstrated 1Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. China. 2Department of Endocrinology and Metabolism, The to repress the transcription of their downstream targets (11). As € fi First Affiliated Hospital of China Medical University, Shenyang, P.R. China. 3Key amemberoftheKruppel C2H2-type zinc nger protein family, Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated the zinc finger protein 677 (ZNF677)istheleaststudied,andis Hospital of Xi'an Jiaotong University, Xi'an, P.R. China. 4Center for Translational onlyfoundtobemethylatedinnon–smallcelllungcancer Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, P.R. (NSCLC;ref.12).However,itsroleinhumancancers,including China. thyroid cancer, remains totally unclear. Note: Supplementary data for this article are available at Cancer Research In this study, we observe that ZNF677 is frequently down- Online (http://cancerres.aacrjournals.org/). regulated by promoter methylation in papillary thyroid cancers Corresponding Authors: Peng Hou, Department of Endocrinology, The First (PTC) and find a significant association of decreased expression Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China. Phone: of ZNF677 with poor patient survival. Functional studies show 8629-8532-4749; Fax: 8629-8532-4039; E-mail: [email protected]; and Meiju Ji, that ZNF677 plays a tumor suppressor role in thyroid cancer cells. [email protected]. Mechanistically, ZNF677 inhibits thyroid tumorigenesis through doi: 10.1158/0008-5472.CAN-18-0003 transcriptionally repressing its downstream targets CDKN3 and Ó2018 American Association for Cancer Research. HSPB1, and subsequently inhibiting Akt phosphorylation. 5216 Cancer Res; 78(18) September 15, 2018 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst July 11, 2018; DOI: 10.1158/0008-5472.CAN-18-0003 ZNF677 Is a Tumor Suppressor in Thyroid Cancer Materials and Methods Expression plasmids, short interfering RNAs, and lentivirus transfection Clinical samples ZNF677 expression plasmid pcDNA3.1(À)A-ZNF677 and A total of 178 paraffin-embedded PTCs and 23 normal empty vector pcDNA3.1(À)AwithaMyc-Histag(Invitrogen) thyroid tissues as control subjects were randomly obtained were obtained from Yingrun Biotechnology, Co., Ltd. The from the First Affiliated Hospital of Xi'an Jiaotong University. primers used for pcDNA3.1-ZNF677 (-CDKN3 or -HSPB1) Clinicopathologic characteristics of the tumors were shown in plasmid construction were shown in Supplementary Table Supplementary Table S1. Moreover, 17 pairs of frozen surgical S5. Cells were transfected with the indicated constructs at PTC and matched noncancerous tissues were also obtained 70% confluence using X-tremeGENE HP DNA Transfection from the First Affiliated Hospital of Xi'an Jiaotong University. Reagent (Invitrogen). These patients did not receive any therapeutic intervention, and Oligonucleotides of siRNA targeting ZNF677, HSPB1, and signed an informed consent before surgery. All of the tissues CDKN3, and control siRNA were obtained from Gene Pharma were histologically examined by two senior pathologists at and Ribobio, respectively. The sequences were presented in Sup- Department of Pathology of the Hospital based on World plementary Table S6. Cells were transfected at 50% confluence Health Organization (WHO) criteria. The study was conducted using Lipofectamine 2000 (Invitrogen) with a final siRNA con- in accordance with the Declaration of Helsinki, and the pro- centration of 50 nmol/L. tocol was approved by the Institutional Review Board and Lentivirus encoding ZNF677 (PHBLV-GFP-Puro-ZNF677), Human Ethics Committee of the First Affiliated Hospital of control lentivirus (PHBLV-GFP-Puro), ZNF677-shRNA (sh- Xi'an Jiaotong University. ZNF677), and control shRNA (sh-NC) were obtained from Han- Bio Biotechnology Co., Ltd. shRNA sequences were also shown in RNA extraction and quantitative RT-PCR Supplementary Table S6. Cells were transfected at 50% confluence RNA isolation, cDNA preparation and qRT-PCR were per- with a final lentivirus multiplicity of infection (MOI) of 20–100 formed as described previously (13). The mRNA expression of for PHBLV and MOI of 20 for shRNAs. the indicated genes was normalized to 18S rRNA cDNA. Each sample was run in triplicate. The primer sequences were presented Cell proliferation, colony formation, cell cycle, apoptosis, in Supplementary Table S2. migration, and invasion assays The procedures for cell proliferation, colony formation, cell- cycle distributions, apoptosis, migration, and invasion assays DNA extraction, methylation-specific PCR, and pyrosequencing were similarly performed as described previously (17). Genomic DNA from cell lines was isolated using a standard phenol–chloroform protocol. Genomic DNA was isolated from Western blot analysis paraffin-embedded tissues as described previously (14). The The detailed protocol was performed as described previously protocols of sodium bisulfite treatment, MSP, and pyrosequen- (17). The antibody information was presented in Supplementary cing were performed as described previously (13, 15). The primer Table S7. sequences for MSP and pyrosequencing were presented in Sup- plementary Tables S2 and S3. Dual-luciferase reporter assay The promoter regions of CDKN3 and HSPB1 genes were Cell lines and drug treatments inserted into predigested pGL3-Basic luciferase vector (Promega) Human thyroid cancer cell lines BCPAP, FTC133, 8505C, to produce the luciferase reporter plasmids pGL3-CDKN3-Luc K1, and TPC1 were provided by Dr. Haixia Guan (The First and pGL3-HSPB1-Luc. The constructs were verified by Sanger Affiliated Hospital of China Medical University, Shenyang, sequencing. The primers for plasmid constructs were presented China). C643 was obtained
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