Identification of cathepsin B as a novel target of hypoxia-inducible factor-1-alpha in HepG2 cells
Hypoxia-inducible factor-1-alpha (HIF-1α) activates the transcription of many genes that code for proteins involved in angiogenesis, glucose metabolism, cell proliferation/survival, and invasion/metastasis. However, the mechanisms between HIF-1 and its downstream target genes are still poorly unders...
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Published in | Biochemical and biophysical research communications Vol. 503; no. 2; pp. 1057 - 1062 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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05.09.2018
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Abstract | Hypoxia-inducible factor-1-alpha (HIF-1α) activates the transcription of many genes that code for proteins involved in angiogenesis, glucose metabolism, cell proliferation/survival, and invasion/metastasis. However, the mechanisms between HIF-1 and its downstream target genes are still poorly understood. Our experimental results had shown that nuclear HIF-1α proteins were significantly induced after HepG2 cells treatment with 1% O2 for 6 h and reached the peak expression level in 24 h. Meanwhile, the results of RT-qPCR and Western-blotting showed that HIF-1α and cathepsin B (CTSB) expressions increased with a similar pattern in response to hypoxia in the HepG2 cells. Additionally, based on bioinformatics analysis, we identified a hypoxia response element in the CTSB promoter, indicating a possible association between HIF-1α and CTSB. Moreover, luciferase assay was performed to reflect the transcriptional activity mediated through the HIF-1α binding HRE within the CTSB promoter. Furthermore, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (CHIP) revealed a specific HIF-1α binding activity to the CTSB gene promoter. For the first time, we demonstrated that CTSB is a new HIF-1α-target gene. We believe these findings will contribute to the research and development of neoplasm-targeted therapies.
•Cathepsin B (CTSB) is a novel target gene of hypoxia-inducible factor-1-alpha (HIF-1α).•CTSB mRNA and protein levels can be up-regulated in a HIF-1α-dependent manner.•CTSB promoter activity can be elevated by the HIF-1α protein.•HIF-1α protein binds the CTSB promoter directly. |
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AbstractList | Hypoxia-inducible factor-1-alpha (HIF-1α) activates the transcription of many genes that code for proteins involved in angiogenesis, glucose metabolism, cell proliferation/survival, and invasion/metastasis. However, the mechanisms between HIF-1 and its downstream target genes are still poorly understood. Our experimental results had shown that nuclear HIF-1α proteins were significantly induced after HepG2 cells treatment with 1% O2 for 6 h and reached the peak expression level in 24 h. Meanwhile, the results of RT-qPCR and Western-blotting showed that HIF-1α and cathepsin B (CTSB) expressions increased with a similar pattern in response to hypoxia in the HepG2 cells. Additionally, based on bioinformatics analysis, we identified a hypoxia response element in the CTSB promoter, indicating a possible association between HIF-1α and CTSB. Moreover, luciferase assay was performed to reflect the transcriptional activity mediated through the HIF-1α binding HRE within the CTSB promoter. Furthermore, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (CHIP) revealed a specific HIF-1α binding activity to the CTSB gene promoter. For the first time, we demonstrated that CTSB is a new HIF-1α-target gene. We believe these findings will contribute to the research and development of neoplasm-targeted therapies.
•Cathepsin B (CTSB) is a novel target gene of hypoxia-inducible factor-1-alpha (HIF-1α).•CTSB mRNA and protein levels can be up-regulated in a HIF-1α-dependent manner.•CTSB promoter activity can be elevated by the HIF-1α protein.•HIF-1α protein binds the CTSB promoter directly. Hypoxia-inducible factor-1-alpha (HIF-1α) activates the transcription of many genes that code for proteins involved in angiogenesis, glucose metabolism, cell proliferation/survival, and invasion/metastasis. However, the mechanisms between HIF-1 and its downstream target genes are still poorly understood. Our experimental results had shown that nuclear HIF-1α proteins were significantly induced after HepG2 cells treatment with 1% O2 for 6 h and reached the peak expression level in 24 h. Meanwhile, the results of RT-qPCR and Western-blotting showed that HIF-1α and cathepsin B (CTSB) expressions increased with a similar pattern in response to hypoxia in the HepG2 cells. Additionally, based on bioinformatics analysis, we identified a hypoxia response element in the CTSB promoter, indicating a possible association between HIF-1α and CTSB. Moreover, luciferase assay was performed to reflect the transcriptional activity mediated through the HIF-1α binding HRE within the CTSB promoter. Furthermore, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (CHIP) revealed a specific HIF-1α binding activity to the CTSB gene promoter. For the first time, we demonstrated that CTSB is a new HIF-1α-target gene. We believe these findings will contribute to the research and development of neoplasm-targeted therapies. Hypoxia-inducible factor-1-alpha (HIF-1α) activates the transcription of many genes that code for proteins involved in angiogenesis, glucose metabolism, cell proliferation/survival, and invasion/metastasis. However, the mechanisms between HIF-1 and its downstream target genes are still poorly understood. Our experimental results had shown that nuclear HIF-1α proteins were significantly induced after HepG2 cells treatment with 1% O for 6 h and reached the peak expression level in 24 h. Meanwhile, the results of RT-qPCR and Western-blotting showed that HIF-1α and cathepsin B (CTSB) expressions increased with a similar pattern in response to hypoxia in the HepG2 cells. Additionally, based on bioinformatics analysis, we identified a hypoxia response element in the CTSB promoter, indicating a possible association between HIF-1α and CTSB. Moreover, luciferase assay was performed to reflect the transcriptional activity mediated through the HIF-1α binding HRE within the CTSB promoter. Furthermore, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (CHIP) revealed a specific HIF-1α binding activity to the CTSB gene promoter. For the first time, we demonstrated that CTSB is a new HIF-1α-target gene. We believe these findings will contribute to the research and development of neoplasm-targeted therapies. Highlights: • Cathepsin B (CTSB) is a novel target gene of hypoxia-inducible factor-1-alpha (HIF-1α). • CTSB mRNA and protein levels can be up-regulated in a HIF-1α-dependent manner. • CTSB promoter activity can be elevated by the HIF-1α protein. • HIF-1α protein binds the CTSB promoter directly. Hypoxia-inducible factor-1-alpha (HIF-1α) activates the transcription of many genes that code for proteins involved in angiogenesis, glucose metabolism, cell proliferation/survival, and invasion/metastasis. However, the mechanisms between HIF-1 and its downstream target genes are still poorly understood. Our experimental results had shown that nuclear HIF-1α proteins were significantly induced after HepG2 cells treatment with 1% O{sub 2} for 6 h and reached the peak expression level in 24 h. Meanwhile, the results of RT-qPCR and Western-blotting showed that HIF-1α and cathepsin B (CTSB) expressions increased with a similar pattern in response to hypoxia in the HepG2 cells. Additionally, based on bioinformatics analysis, we identified a hypoxia response element in the CTSB promoter, indicating a possible association between HIF-1α and CTSB. Moreover, luciferase assay was performed to reflect the transcriptional activity mediated through the HIF-1α binding HRE within the CTSB promoter. Furthermore, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (CHIP) revealed a specific HIF-1α binding activity to the CTSB gene promoter. For the first time, we demonstrated that CTSB is a new HIF-1α-target gene. We believe these findings will contribute to the research and development of neoplasm-targeted therapies. |
Author | Feng, Zhao Xiaofei, Cheng Dongkai, Zhou Yanqing, Li Dong, Chen Weilin, Wang |
Author_xml | – sequence: 1 givenname: Cheng surname: Xiaofei fullname: Xiaofei, Cheng organization: Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China – sequence: 2 givenname: Li surname: Yanqing fullname: Yanqing, Li organization: Department of Pathology, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China – sequence: 3 givenname: Zhou orcidid: 0000-0003-0705-9796 surname: Dongkai fullname: Dongkai, Zhou organization: Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China – sequence: 4 givenname: Chen surname: Dong fullname: Dong, Chen organization: Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China – sequence: 5 givenname: Zhao surname: Feng fullname: Feng, Zhao organization: Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China – sequence: 6 givenname: Wang surname: Weilin fullname: Weilin, Wang email: wam@zju.edu.cn organization: Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China |
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Keywords | Cathepsin B (CTSB) Transcription Hypoxia-inducible factor-1-alpha (HIF-1α) Target gene |
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Snippet | Hypoxia-inducible factor-1-alpha (HIF-1α) activates the transcription of many genes that code for proteins involved in angiogenesis, glucose metabolism, cell... Highlights: • Cathepsin B (CTSB) is a novel target gene of hypoxia-inducible factor-1-alpha (HIF-1α). • CTSB mRNA and protein levels can be up-regulated in a... |
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SubjectTerms | 60 APPLIED LIFE SCIENCES ANGIOGENESIS Cathepsin B (CTSB) Cathepsin B - genetics CATHEPSINS Cell Hypoxia CELL PROLIFERATION GLUCOSE Hep G2 Cells Humans Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Hypoxia-inducible factor-1-alpha (HIF-1α) LUCIFERASE MESSENGER-RNA NEOPLASMS Oxygen - metabolism Promoter Regions, Genetic Response Elements Target gene Transcription Transcriptional Activation Up-Regulation |
Title | Identification of cathepsin B as a novel target of hypoxia-inducible factor-1-alpha in HepG2 cells |
URI | https://dx.doi.org/10.1016/j.bbrc.2018.06.116 https://www.ncbi.nlm.nih.gov/pubmed/29935187 https://search.proquest.com/docview/2058507663 https://www.osti.gov/biblio/23105634 |
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