Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation

Yubin Lei,Jiucun Wang,Lingling Liu,Shujing Zhang,Shicheng Guo,Xiaofeng Chen,Hengning Ke,Xiaoqing Li,Wufan Tao,Bo Su,Yuchao Fang

doi:10.1186/s12943-017-0736-2

Abstract

BackgroundLung 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.MethodsHdac7+/−/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.ResultsThe 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.ConclusionOur 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.

Highlights

Lung cancer is the leading cause of cancer death worldwide
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
The results showed that total tumor numbers on mouse lung surface (Fig. 1c) and tumor burden (Fig. 1d) were markedly reduced in Hdac7+/−/Kirsten rat sarcoma viral oncogene homolog (K-Ras) mice compared with control mice

Summary

Introduction

Lung cancer is the leading cause of cancer death worldwide. the molecular mechanisms underlying lung cancer development have not been fully understood. Methods: Hdac7+/−/K-Ras mice and HDAC7-depleted human lung cancer cell lines were used as models for studying the function of Hdac gene in lung cancer. In Hdac7+/−/K-Ras mice, cell proliferation was significantly inhibited and apoptosis in lung tumors was greatly enhanced. Cell proliferation and anchorage-independent growth of human lung cancer cell lines expressing shHDAC7 were significantly suppressed and apoptosis was dramatically elevated respectively. Mechanistic study revealed that Hdac mutation in mouse lung tumors or HDAC7 depletion in human tumor cell lines resulted in significantly enhanced acetylation and tyrosine-phosphorylation of Stat and HDAC7 protein directly interacted with and deacetylateed STAT3. The Hdac 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 dnStat. Hdac and Hdac function as tumor suppressors on preleukemic stage, but oncogenes for leukemia maintenance in PML-RAR-mediated mouse acute promyelocytic leukemia [8]

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Discussion

Conclusion