14–3-3ζ inhibits heme oxygenase-1 (HO-1) degradation and promotes hepatocellular carcinoma proliferation: involvement of STAT3 signaling
Abstract Background Heme oxygenase 1 (HO-1) has been reported to be very important in the pathogenesis or progression of multiple types of cancer. Identification of novel hmox1 binding proteins may reveal undefined oncogenes, tumor suppressors, signaling pathways, and possible treatment targets. Met...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-018-1007-9 |
| _version_ | 1819199993976717312 |
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| author | Jia Song Xiaochao Zhang Zhibin Liao Huifang Liang Liang Chu Wei Dong Xuewu Zhang Qianyun Ge Qiumeng Liu Pan Fan Zhanguo Zhang Bixiang Zhang |
| author_facet | Jia Song Xiaochao Zhang Zhibin Liao Huifang Liang Liang Chu Wei Dong Xuewu Zhang Qianyun Ge Qiumeng Liu Pan Fan Zhanguo Zhang Bixiang Zhang |
| author_sort | Jia Song |
| collection | DOAJ |
| description | Abstract Background Heme oxygenase 1 (HO-1) has been reported to be very important in the pathogenesis or progression of multiple types of cancer. Identification of novel hmox1 binding proteins may reveal undefined oncogenes, tumor suppressors, signaling pathways, and possible treatment targets. Methods Immunoprecipitation and mass spectrometry analyses were used to identify novel regulators of HO-1. The association of the 14–3-3ζ protein with HO-1 and modulation of the stability of HO-1 were investigated by co-immunoprecipitation, immunofluorescence, western blotting, and quantitative RT-PCR. Degradation and in vivo ubiquitination assays were utilized to examine whether 14–3-3ζ stabilizes the HO-1 protein by inhibiting its ubiquitination. The effect of 14–3-3ζ on proliferation was investigated by function assays conducted in vitro using the CCK-8 and colony formation assays and in vivo in a xenograft mouse model. The biological functions of the 14–3-3ζ/HO-1 axis were demonstrated by western blotting and rescue experiments. Using gain-of-function and loss-of-function strategies, we further clarified the impact of 14–3-3ζ/HO-1 complex on the signal transducers and activators of transcription 3 (STAT3) signaling pathway in cancer cells. Results We identified 14–3-3ζ as a novel HO-1 binding protein. The binding inhibited the ubiquitination and proteasome-mediated degradation of HO-1, thus facilitating its stabilization. Enforced expression of 14–3-3ζ significantly promoted cell proliferation in vitro, as well as tumorigenesis in vivo, while 14–3-3ζ knockdown had opposite effects. The data indicated that 14–3-3ζ can stabilize HO-1 expression and thus influence cancer cell proliferation. We further demonstrated the involvement of the STAT3 pathway in 14–3-3ζ/HO-1 regulation of hepatocellular carcinoma cell proliferation. Conclusions Collectively, these data show that 14–3-3ζ regulates the stability of HO-1 to promote cancer cell proliferation and STAT3 signaling activation. The data establish the 14–3-3ζ-HO-1-STAT3 axis as an important regulatory mechanism of cancer cell growth and implicate HO-1 and 14–3-3ζ as potential therapeutic targets in hepatocellular carcinoma. |
| first_indexed | 2024-12-23T03:25:10Z |
| format | Article |
| id | doaj.art-70833c71b23c4ce4b8d06a4a86cb7d6c |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-23T03:25:10Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-70833c71b23c4ce4b8d06a4a86cb7d6c2022-12-21T18:01:52ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-01-0138111510.1186/s13046-018-1007-914–3-3ζ inhibits heme oxygenase-1 (HO-1) degradation and promotes hepatocellular carcinoma proliferation: involvement of STAT3 signalingJia Song0Xiaochao Zhang1Zhibin Liao2Huifang Liang3Liang Chu4Wei Dong5Xuewu Zhang6Qianyun Ge7Qiumeng Liu8Pan Fan9Zhanguo Zhang10Bixiang Zhang11Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Heme oxygenase 1 (HO-1) has been reported to be very important in the pathogenesis or progression of multiple types of cancer. Identification of novel hmox1 binding proteins may reveal undefined oncogenes, tumor suppressors, signaling pathways, and possible treatment targets. Methods Immunoprecipitation and mass spectrometry analyses were used to identify novel regulators of HO-1. The association of the 14–3-3ζ protein with HO-1 and modulation of the stability of HO-1 were investigated by co-immunoprecipitation, immunofluorescence, western blotting, and quantitative RT-PCR. Degradation and in vivo ubiquitination assays were utilized to examine whether 14–3-3ζ stabilizes the HO-1 protein by inhibiting its ubiquitination. The effect of 14–3-3ζ on proliferation was investigated by function assays conducted in vitro using the CCK-8 and colony formation assays and in vivo in a xenograft mouse model. The biological functions of the 14–3-3ζ/HO-1 axis were demonstrated by western blotting and rescue experiments. Using gain-of-function and loss-of-function strategies, we further clarified the impact of 14–3-3ζ/HO-1 complex on the signal transducers and activators of transcription 3 (STAT3) signaling pathway in cancer cells. Results We identified 14–3-3ζ as a novel HO-1 binding protein. The binding inhibited the ubiquitination and proteasome-mediated degradation of HO-1, thus facilitating its stabilization. Enforced expression of 14–3-3ζ significantly promoted cell proliferation in vitro, as well as tumorigenesis in vivo, while 14–3-3ζ knockdown had opposite effects. The data indicated that 14–3-3ζ can stabilize HO-1 expression and thus influence cancer cell proliferation. We further demonstrated the involvement of the STAT3 pathway in 14–3-3ζ/HO-1 regulation of hepatocellular carcinoma cell proliferation. Conclusions Collectively, these data show that 14–3-3ζ regulates the stability of HO-1 to promote cancer cell proliferation and STAT3 signaling activation. The data establish the 14–3-3ζ-HO-1-STAT3 axis as an important regulatory mechanism of cancer cell growth and implicate HO-1 and 14–3-3ζ as potential therapeutic targets in hepatocellular carcinoma.http://link.springer.com/article/10.1186/s13046-018-1007-914–3-3ζHO-1ProliferationSTAT3Hepatocellular carcinoma |
| spellingShingle | Jia Song Xiaochao Zhang Zhibin Liao Huifang Liang Liang Chu Wei Dong Xuewu Zhang Qianyun Ge Qiumeng Liu Pan Fan Zhanguo Zhang Bixiang Zhang 14–3-3ζ inhibits heme oxygenase-1 (HO-1) degradation and promotes hepatocellular carcinoma proliferation: involvement of STAT3 signaling Journal of Experimental & Clinical Cancer Research 14–3-3ζ HO-1 Proliferation STAT3 Hepatocellular carcinoma |
| title | 14–3-3ζ inhibits heme oxygenase-1 (HO-1) degradation and promotes hepatocellular carcinoma proliferation: involvement of STAT3 signaling |
| title_full | 14–3-3ζ inhibits heme oxygenase-1 (HO-1) degradation and promotes hepatocellular carcinoma proliferation: involvement of STAT3 signaling |
| title_fullStr | 14–3-3ζ inhibits heme oxygenase-1 (HO-1) degradation and promotes hepatocellular carcinoma proliferation: involvement of STAT3 signaling |
| title_full_unstemmed | 14–3-3ζ inhibits heme oxygenase-1 (HO-1) degradation and promotes hepatocellular carcinoma proliferation: involvement of STAT3 signaling |
| title_short | 14–3-3ζ inhibits heme oxygenase-1 (HO-1) degradation and promotes hepatocellular carcinoma proliferation: involvement of STAT3 signaling |
| title_sort | 14 3 3ζ inhibits heme oxygenase 1 ho 1 degradation and promotes hepatocellular carcinoma proliferation involvement of stat3 signaling |
| topic | 14–3-3ζ HO-1 Proliferation STAT3 Hepatocellular carcinoma |
| url | http://link.springer.com/article/10.1186/s13046-018-1007-9 |
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