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ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma

BACKGROUND: Tumor metastasis is the major reason for poor prognosis of hepatocellular carcinoma (HCC) patients after hepatic resection. SMYD3 has been demonstrated to promote liver tumor metastasis in mice. However, the detailed molecular mechanism is still largely unknown. METHODS: The effect of SM...

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Autores principales: Zhou, Zhenyu, Jiang, Hai, Tu, Kangsheng, Yu, Wei, Zhang, Jianlong, Hu, Zhigang, Zhang, Heyun, Hao, Dake, Huang, Pinbo, Wang, Jie, Wang, Aijun, Xiao, Zhiyu, He, Chuanchao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332640/
https://www.ncbi.nlm.nih.gov/pubmed/30646949
http://dx.doi.org/10.1186/s13046-018-1011-0
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author Zhou, Zhenyu
Jiang, Hai
Tu, Kangsheng
Yu, Wei
Zhang, Jianlong
Hu, Zhigang
Zhang, Heyun
Hao, Dake
Huang, Pinbo
Wang, Jie
Wang, Aijun
Xiao, Zhiyu
He, Chuanchao
author_facet Zhou, Zhenyu
Jiang, Hai
Tu, Kangsheng
Yu, Wei
Zhang, Jianlong
Hu, Zhigang
Zhang, Heyun
Hao, Dake
Huang, Pinbo
Wang, Jie
Wang, Aijun
Xiao, Zhiyu
He, Chuanchao
author_sort Zhou, Zhenyu
collection PubMed
description BACKGROUND: Tumor metastasis is the major reason for poor prognosis of hepatocellular carcinoma (HCC) patients after hepatic resection. SMYD3 has been demonstrated to promote liver tumor metastasis in mice. However, the detailed molecular mechanism is still largely unknown. METHODS: The effect of SMYD3 on invasiveness and metastasis of HCC was analyzed by immunohistochemistry, migration assay, invasion assay, wound healing assay and in vivo lung metastasis assay. Mass spectrometry analysis was conducted using proteins pulled down by H3K4me3 antibody in SMYD3-overexpressing cells. Luciferase reporter, chromatin immunoprecipitation, Electrophoretic mobility shift assay were used to measure the regulation of SLUG transcription by SMYD3-ANKHD1. In addition, the role of SMYD3-ANKHD1 in determining clinical outcomes for HCC patients was investigated by immunohistochemistry in 243 HCC tissues. RESULTS: SMYD3 was an independent prognostic factor of HCC and promoted migration and invasion of human HCC cells. ANKHD1 was identified by mass spectrometry as a co-regulator with SMYD3. ANKHD1 interacted with H3K4me3 when cells were overexpressing SMYD3. The pro-migratory and pro-invasive effects of SMYD3 were attenuated when ANKHD1 was knocked down by siRNA. Furthermore, we found that SMYD3 bound and activated the SLUG gene promoter in a manner associated with elevating H3K4me3, H3K9Ac and H3K14Ac. Knockdown of ANKHD1 could attenuate the SMYD3-dependent activation of Slug expression. We further detected the expression of SMYD3 and ANKHD1 in 243 HCC patients and found that patients with positive coexpression of SMYD3 and ANKHD1 (SMYD3(+)ANKHD1(+)) had the shortest overall and recurrence-free survival. CONCLUSION: Our findings provide a novel molecular mechanism for the SMYD3-regulated HCC migration and metastasis, and indicates that SMYD3-ANKHD1 may be a potential target for treating HCC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-018-1011-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-63326402019-01-16 ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma Zhou, Zhenyu Jiang, Hai Tu, Kangsheng Yu, Wei Zhang, Jianlong Hu, Zhigang Zhang, Heyun Hao, Dake Huang, Pinbo Wang, Jie Wang, Aijun Xiao, Zhiyu He, Chuanchao J Exp Clin Cancer Res Research BACKGROUND: Tumor metastasis is the major reason for poor prognosis of hepatocellular carcinoma (HCC) patients after hepatic resection. SMYD3 has been demonstrated to promote liver tumor metastasis in mice. However, the detailed molecular mechanism is still largely unknown. METHODS: The effect of SMYD3 on invasiveness and metastasis of HCC was analyzed by immunohistochemistry, migration assay, invasion assay, wound healing assay and in vivo lung metastasis assay. Mass spectrometry analysis was conducted using proteins pulled down by H3K4me3 antibody in SMYD3-overexpressing cells. Luciferase reporter, chromatin immunoprecipitation, Electrophoretic mobility shift assay were used to measure the regulation of SLUG transcription by SMYD3-ANKHD1. In addition, the role of SMYD3-ANKHD1 in determining clinical outcomes for HCC patients was investigated by immunohistochemistry in 243 HCC tissues. RESULTS: SMYD3 was an independent prognostic factor of HCC and promoted migration and invasion of human HCC cells. ANKHD1 was identified by mass spectrometry as a co-regulator with SMYD3. ANKHD1 interacted with H3K4me3 when cells were overexpressing SMYD3. The pro-migratory and pro-invasive effects of SMYD3 were attenuated when ANKHD1 was knocked down by siRNA. Furthermore, we found that SMYD3 bound and activated the SLUG gene promoter in a manner associated with elevating H3K4me3, H3K9Ac and H3K14Ac. Knockdown of ANKHD1 could attenuate the SMYD3-dependent activation of Slug expression. We further detected the expression of SMYD3 and ANKHD1 in 243 HCC patients and found that patients with positive coexpression of SMYD3 and ANKHD1 (SMYD3(+)ANKHD1(+)) had the shortest overall and recurrence-free survival. CONCLUSION: Our findings provide a novel molecular mechanism for the SMYD3-regulated HCC migration and metastasis, and indicates that SMYD3-ANKHD1 may be a potential target for treating HCC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-018-1011-0) contains supplementary material, which is available to authorized users. BioMed Central 2019-01-15 /pmc/articles/PMC6332640/ /pubmed/30646949 http://dx.doi.org/10.1186/s13046-018-1011-0 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Zhou, Zhenyu
Jiang, Hai
Tu, Kangsheng
Yu, Wei
Zhang, Jianlong
Hu, Zhigang
Zhang, Heyun
Hao, Dake
Huang, Pinbo
Wang, Jie
Wang, Aijun
Xiao, Zhiyu
He, Chuanchao
ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma
title ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma
title_full ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma
title_fullStr ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma
title_full_unstemmed ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma
title_short ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma
title_sort ankhd1 is required for smyd3 to promote tumor metastasis in hepatocellular carcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332640/
https://www.ncbi.nlm.nih.gov/pubmed/30646949
http://dx.doi.org/10.1186/s13046-018-1011-0
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