Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling
ABSTRACT Hypoxia is linked to therapeutic resistance and poor clinical prognosis for many tumor entities, including human papillomavirus (HPV)-positive cancers. Notably, HPV-positive cancer cells can induce a dormant state under hypoxia, characterized by a reversible growth arrest and strong repress...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2019-02-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.02323-18 |
| _version_ | 1818424716005736448 |
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| author | Felicitas Bossler Bianca J. Kuhn Thomas Günther Stephen J. Kraemer Prajakta Khalkar Svenja Adrian Claudia Lohrey Angela Holzer Mitsugu Shimobayashi Matthias Dürst Arnulf Mayer Frank Rösl Adam Grundhoff Jeroen Krijgsveld Karin Hoppe-Seyler Felix Hoppe-Seyler |
| author_facet | Felicitas Bossler Bianca J. Kuhn Thomas Günther Stephen J. Kraemer Prajakta Khalkar Svenja Adrian Claudia Lohrey Angela Holzer Mitsugu Shimobayashi Matthias Dürst Arnulf Mayer Frank Rösl Adam Grundhoff Jeroen Krijgsveld Karin Hoppe-Seyler Felix Hoppe-Seyler |
| author_sort | Felicitas Bossler |
| collection | DOAJ |
| description | ABSTRACT Hypoxia is linked to therapeutic resistance and poor clinical prognosis for many tumor entities, including human papillomavirus (HPV)-positive cancers. Notably, HPV-positive cancer cells can induce a dormant state under hypoxia, characterized by a reversible growth arrest and strong repression of viral E6/E7 oncogene expression, which could contribute to therapy resistance, immune evasion and tumor recurrence. The present work aimed to gain mechanistic insights into the pathway(s) underlying HPV oncogene repression under hypoxia. We show that E6/E7 downregulation is mediated by hypoxia-induced stimulation of AKT signaling. Ablating AKT function in hypoxic HPV-positive cancer cells by using chemical inhibitors efficiently counteracts E6/E7 repression. Isoform-specific activation or downregulation of AKT1 and AKT2 reveals that both AKT isoforms contribute to hypoxic E6/E7 repression and act in a functionally redundant manner. Hypoxic AKT activation and consecutive E6/E7 repression is dependent on the activities of the canonical upstream AKT regulators phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) complex 2 (mTORC2). Hypoxic downregulation of E6/E7 occurs, at least in part, at the transcriptional level. Modulation of E6/E7 expression by the PI3K/mTORC2/AKT cascade is hypoxia specific and not observed in normoxic HPV-positive cancer cells. Quantitative proteome analyses identify additional factors as candidates to be involved in hypoxia-induced activation of the PI3K/mTORC2/AKT signaling cascade and in the AKT-dependent repression of the E6/E7 oncogenes under hypoxia. Collectively, these data uncover a functional key role of the PI3K/mTORC2/AKT signaling cascade for viral oncogene repression in hypoxic HPV-positive cancer cells and provide new insights into the poorly understood cross talk between oncogenic HPVs and their host cells under hypoxia. IMPORTANCE Oncogenic HPV types are major human carcinogens. Under hypoxia, HPV-positive cancer cells can repress the viral E6/E7 oncogenes and induce a reversible growth arrest. This response could contribute to therapy resistance, immune evasion, and tumor recurrence upon reoxygenation. Here, we uncover evidence that HPV oncogene repression is mediated by hypoxia-induced activation of canonical PI3K/mTORC2/AKT signaling. AKT-dependent downregulation of E6/E7 is only observed under hypoxia and occurs, at least in part, at the transcriptional level. Quantitative proteome analyses identify additional factors as candidates to be involved in AKT-dependent E6/E7 repression and/or hypoxic PI3K/mTORC2/AKT activation. These results connect PI3K/mTORC2/AKT signaling with HPV oncogene regulation, providing new mechanistic insights into the cross talk between oncogenic HPVs and their host cells. |
| first_indexed | 2024-12-14T14:02:27Z |
| format | Article |
| id | doaj.art-918e7614f6584952bcd19da40a198aa4 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-14T14:02:27Z |
| publishDate | 2019-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-918e7614f6584952bcd19da40a198aa42022-12-21T22:58:42ZengAmerican Society for MicrobiologymBio2150-75112019-02-0110110.1128/mBio.02323-18Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT SignalingFelicitas Bossler0Bianca J. Kuhn1Thomas Günther2Stephen J. Kraemer3Prajakta Khalkar4Svenja Adrian5Claudia Lohrey6Angela Holzer7Mitsugu Shimobayashi8Matthias Dürst9Arnulf Mayer10Frank Rösl11Adam Grundhoff12Jeroen Krijgsveld13Karin Hoppe-Seyler14Felix Hoppe-Seyler15Molecular Therapy of Virus-Associated Cancers, German Cancer Research Center (DKFZ), Heidelberg, GermanyFaculty of Biosciences, Heidelberg University, Heidelberg, GermanyHeinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, GermanyFaculty of Biosciences, Heidelberg University, Heidelberg, GermanyFaculty of Biosciences, Heidelberg University, Heidelberg, GermanyMolecular Therapy of Virus-Associated Cancers, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Therapy of Virus-Associated Cancers, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Therapy of Virus-Associated Cancers, German Cancer Research Center (DKFZ), Heidelberg, GermanyBiozentrum University of Basel, Basel, SwitzerlandDepartment of Gynaecology, Jena University Hospital, Jena, GermanyDepartment of Radiooncology and Radiotherapy, Mainz University Medical Center, Mainz, GermanyViral Transformation Mechanisms, German Cancer Research Center (DKFZ), Heidelberg, GermanyHeinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, GermanyDivision of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Therapy of Virus-Associated Cancers, German Cancer Research Center (DKFZ), Heidelberg, GermanyMolecular Therapy of Virus-Associated Cancers, German Cancer Research Center (DKFZ), Heidelberg, GermanyABSTRACT Hypoxia is linked to therapeutic resistance and poor clinical prognosis for many tumor entities, including human papillomavirus (HPV)-positive cancers. Notably, HPV-positive cancer cells can induce a dormant state under hypoxia, characterized by a reversible growth arrest and strong repression of viral E6/E7 oncogene expression, which could contribute to therapy resistance, immune evasion and tumor recurrence. The present work aimed to gain mechanistic insights into the pathway(s) underlying HPV oncogene repression under hypoxia. We show that E6/E7 downregulation is mediated by hypoxia-induced stimulation of AKT signaling. Ablating AKT function in hypoxic HPV-positive cancer cells by using chemical inhibitors efficiently counteracts E6/E7 repression. Isoform-specific activation or downregulation of AKT1 and AKT2 reveals that both AKT isoforms contribute to hypoxic E6/E7 repression and act in a functionally redundant manner. Hypoxic AKT activation and consecutive E6/E7 repression is dependent on the activities of the canonical upstream AKT regulators phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) complex 2 (mTORC2). Hypoxic downregulation of E6/E7 occurs, at least in part, at the transcriptional level. Modulation of E6/E7 expression by the PI3K/mTORC2/AKT cascade is hypoxia specific and not observed in normoxic HPV-positive cancer cells. Quantitative proteome analyses identify additional factors as candidates to be involved in hypoxia-induced activation of the PI3K/mTORC2/AKT signaling cascade and in the AKT-dependent repression of the E6/E7 oncogenes under hypoxia. Collectively, these data uncover a functional key role of the PI3K/mTORC2/AKT signaling cascade for viral oncogene repression in hypoxic HPV-positive cancer cells and provide new insights into the poorly understood cross talk between oncogenic HPVs and their host cells under hypoxia. IMPORTANCE Oncogenic HPV types are major human carcinogens. Under hypoxia, HPV-positive cancer cells can repress the viral E6/E7 oncogenes and induce a reversible growth arrest. This response could contribute to therapy resistance, immune evasion, and tumor recurrence upon reoxygenation. Here, we uncover evidence that HPV oncogene repression is mediated by hypoxia-induced activation of canonical PI3K/mTORC2/AKT signaling. AKT-dependent downregulation of E6/E7 is only observed under hypoxia and occurs, at least in part, at the transcriptional level. Quantitative proteome analyses identify additional factors as candidates to be involved in AKT-dependent E6/E7 repression and/or hypoxic PI3K/mTORC2/AKT activation. These results connect PI3K/mTORC2/AKT signaling with HPV oncogene regulation, providing new mechanistic insights into the cross talk between oncogenic HPVs and their host cells.https://journals.asm.org/doi/10.1128/mBio.02323-18AKTcervical cancerhuman papillomavirustumor virus |
| spellingShingle | Felicitas Bossler Bianca J. Kuhn Thomas Günther Stephen J. Kraemer Prajakta Khalkar Svenja Adrian Claudia Lohrey Angela Holzer Mitsugu Shimobayashi Matthias Dürst Arnulf Mayer Frank Rösl Adam Grundhoff Jeroen Krijgsveld Karin Hoppe-Seyler Felix Hoppe-Seyler Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling mBio AKT cervical cancer human papillomavirus tumor virus |
| title | Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling |
| title_full | Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling |
| title_fullStr | Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling |
| title_full_unstemmed | Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling |
| title_short | Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling |
| title_sort | repression of human papillomavirus oncogene expression under hypoxia is mediated by pi3k mtorc2 akt signaling |
| topic | AKT cervical cancer human papillomavirus tumor virus |
| url | https://journals.asm.org/doi/10.1128/mBio.02323-18 |
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