Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation
Abstract Background Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms underlying lung cancer development have not been fully understood. The functions of histone deacetylases (HDACs), a class of total eighteen proteins (HDAC1–11 and SIRT1–7 in mammals) tha...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2017-11-01
|
Series: | Molecular Cancer |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s12943-017-0736-2 |
id |
doaj-874dc6d822a741a98810a4b8a098cd30 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yubin Lei Lingling Liu Shujing Zhang Shicheng Guo Xiaoqing Li Jiucun Wang Bo Su Yuchao Fang Xiaofeng Chen Hengning Ke Wufan Tao |
spellingShingle |
Yubin Lei Lingling Liu Shujing Zhang Shicheng Guo Xiaoqing Li Jiucun Wang Bo Su Yuchao Fang Xiaofeng Chen Hengning Ke Wufan Tao Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation Molecular Cancer Hdac7 Stat3 Acetylation & phosphorylation Lung cancer |
author_facet |
Yubin Lei Lingling Liu Shujing Zhang Shicheng Guo Xiaoqing Li Jiucun Wang Bo Su Yuchao Fang Xiaofeng Chen Hengning Ke Wufan Tao |
author_sort |
Yubin Lei |
title |
Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation |
title_short |
Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation |
title_full |
Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation |
title_fullStr |
Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation |
title_full_unstemmed |
Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation |
title_sort |
hdac7 promotes lung tumorigenesis by inhibiting stat3 activation |
publisher |
BMC |
series |
Molecular Cancer |
issn |
1476-4598 |
publishDate |
2017-11-01 |
description |
Abstract Background Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms underlying lung cancer development have not been fully understood. The functions of histone deacetylases (HDACs), a class of total eighteen proteins (HDAC1–11 and SIRT1–7 in mammals) that deacetylate histones and non-histone proteins, in cancers are largely unknown. Methods Hdac7 +/−/K-Ras mice and HDAC7-depleted human lung cancer cell lines were used as models for studying the function of Hdac7 gene in lung cancer. Kaplan-Meier survival analysis was performed to explore the relationship between HDAC7 expression and prognosis of human lung cancers. Recombinant lentivirus-mediated in vivo gene expression or knockdown, Western blotting, and pull-down assay were applied to investigate the underlying molecular mechanism by which Hdac7 promotes lung tumorigenesis. Results The number and burden of lung tumor were dramatically reduced in Hdac7 +/−/K-Ras mice compared to control K-Ras mice. Also, in Hdac7 +/−/K-Ras mice, cell proliferation was significantly inhibited and apoptosis in lung tumors was greatly enhanced. Similarly, cell proliferation and anchorage-independent growth of human lung cancer cell lines expressing shHDAC7 were also significantly suppressed and apoptosis was dramatically elevated respectively. Mechanistic study revealed that Hdac7 mutation in mouse lung tumors or HDAC7 depletion in human tumor cell lines resulted in significantly enhanced acetylation and tyrosine-phosphorylation of Stat3 and HDAC7 protein directly interacted with and deacetylateed STAT3. The Hdac7 mutant-mediated inhibitory effects on lung tumorigenesis in mice and cell proliferation/soft agar colony formation of human lung cancer cell lines were respectively reversed by expressing dnStat3. Finally, the high HDAC7 mRNA level was found to be correlated with poor prognosis of human lung cancer patients. Conclusion Our study suggests that Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation via deacetylating Stat3 and may shed a light on the design of new therapeutic strategies for human lung cancer. |
topic |
Hdac7 Stat3 Acetylation & phosphorylation Lung cancer |
url |
http://link.springer.com/article/10.1186/s12943-017-0736-2 |
work_keys_str_mv |
AT yubinlei hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT linglingliu hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT shujingzhang hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT shichengguo hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT xiaoqingli hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT jiucunwang hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT bosu hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT yuchaofang hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT xiaofengchen hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT hengningke hdac7promoteslungtumorigenesisbyinhibitingstat3activation AT wufantao hdac7promoteslungtumorigenesisbyinhibitingstat3activation |
_version_ |
1725187049304096768 |
spelling |
doaj-874dc6d822a741a98810a4b8a098cd302020-11-25T01:07:28ZengBMCMolecular Cancer1476-45982017-11-0116111310.1186/s12943-017-0736-2Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activationYubin Lei0Lingling Liu1Shujing Zhang2Shicheng Guo3Xiaoqing Li4Jiucun Wang5Bo Su6Yuchao Fang7Xiaofeng Chen8Hengning Ke9Wufan Tao10Obstetrics & Gynecology Hospital and State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan UniversityObstetrics & Gynecology Hospital and State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan UniversityObstetrics & Gynecology Hospital and State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan UniversityMOE Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan UniversityObstetrics & Gynecology Hospital and State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan UniversityMOE Key Laboratory of Contemporary Anthropology and Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan UniversityShanghai Pulmonary Hospital, Tongji UniversityHuashan Hospital, Fudan UniversityHuashan Hospital, Fudan UniversityCancer Research Institute, General Hospital, Ningxia Medical UniversityObstetrics & Gynecology Hospital and State Key Laboratory of Genetic Engineering and Institute of Developmental Biology and Molecular Medicine, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan UniversityAbstract Background Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms underlying lung cancer development have not been fully understood. The functions of histone deacetylases (HDACs), a class of total eighteen proteins (HDAC1–11 and SIRT1–7 in mammals) that deacetylate histones and non-histone proteins, in cancers are largely unknown. Methods Hdac7 +/−/K-Ras mice and HDAC7-depleted human lung cancer cell lines were used as models for studying the function of Hdac7 gene in lung cancer. Kaplan-Meier survival analysis was performed to explore the relationship between HDAC7 expression and prognosis of human lung cancers. Recombinant lentivirus-mediated in vivo gene expression or knockdown, Western blotting, and pull-down assay were applied to investigate the underlying molecular mechanism by which Hdac7 promotes lung tumorigenesis. Results The number and burden of lung tumor were dramatically reduced in Hdac7 +/−/K-Ras mice compared to control K-Ras mice. Also, in Hdac7 +/−/K-Ras mice, cell proliferation was significantly inhibited and apoptosis in lung tumors was greatly enhanced. Similarly, cell proliferation and anchorage-independent growth of human lung cancer cell lines expressing shHDAC7 were also significantly suppressed and apoptosis was dramatically elevated respectively. Mechanistic study revealed that Hdac7 mutation in mouse lung tumors or HDAC7 depletion in human tumor cell lines resulted in significantly enhanced acetylation and tyrosine-phosphorylation of Stat3 and HDAC7 protein directly interacted with and deacetylateed STAT3. The Hdac7 mutant-mediated inhibitory effects on lung tumorigenesis in mice and cell proliferation/soft agar colony formation of human lung cancer cell lines were respectively reversed by expressing dnStat3. Finally, the high HDAC7 mRNA level was found to be correlated with poor prognosis of human lung cancer patients. Conclusion Our study suggests that Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation via deacetylating Stat3 and may shed a light on the design of new therapeutic strategies for human lung cancer.http://link.springer.com/article/10.1186/s12943-017-0736-2Hdac7Stat3Acetylation & phosphorylationLung cancer |