c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer
Abstract Autophagy is important for the removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-11-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06248-3 |
| _version_ | 1827770291580829696 |
|---|---|
| author | Alessandro Medda Micaela Compagnoni Giorgio Spini Simona Citro Ottavio Croci Stefano Campaner Marta Tagliabue Mohssen Ansarin Susanna Chiocca |
| author_facet | Alessandro Medda Micaela Compagnoni Giorgio Spini Simona Citro Ottavio Croci Stefano Campaner Marta Tagliabue Mohssen Ansarin Susanna Chiocca |
| author_sort | Alessandro Medda |
| collection | DOAJ |
| description | Abstract Autophagy is important for the removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus (HPV) positive cancers. HPV infection is a major risk factor in a subset of head and neck cancer (HNC), for which no targeted therapies are currently available. Herein, we assessed autophagy function in HPV-positive HNC. We showed that HPV-positive HNC cells presented a transcriptional and functional impairment of the autophagic process compared to HPV-negative cells, which were reactivated by knocking down HPV E6/E7 oncoproteins, the drivers of cellular transformation. We found that the oncoprotein c-MYC was stabilized and triggered in HPV-positive cell lines. This resulted in the reduced binding of the MiT/TFE transcription factors to their autophagy targets due to c-MYC competition. Thus, the knock-down of c-MYC induced the upregulation of autophagic and lysosomal genes in HPV-positive HNC cells, as well as the increase of autophagic markers at the protein level. Moreover, HPV oncoprotein E7 upregulated the expression of the phosphatase inhibitor CIP2A, accounting for c-MYC upregulation and stability in HPV+ HNC cells. CIP2A mRNA expression negatively correlated with autophagy gene expression in tumor tissues from HNC patients, showing, for the first time, its implication in a transcriptional autophagic context. Both CIP2A and c-MYC knock-down, as well as pharmacological downregulation of c-MYC, resulted in increased resistance to cisplatin treatment. Our results not only show a novel way by which HPV oncoproteins manipulate the host machinery but also provide more insights into the role of autophagy in chemoresistance, with possible implications for targeted HPV-positive HNC therapy. |
| first_indexed | 2024-03-11T12:37:30Z |
| format | Article |
| id | doaj.art-4066af2095a245c09304890534c16384 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-11T12:37:30Z |
| publishDate | 2023-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-4066af2095a245c09304890534c163842023-11-05T12:30:53ZengNature Publishing GroupCell Death and Disease2041-48892023-11-01141111410.1038/s41419-023-06248-3c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancerAlessandro Medda0Micaela Compagnoni1Giorgio Spini2Simona Citro3Ottavio Croci4Stefano Campaner5Marta Tagliabue6Mohssen Ansarin7Susanna Chiocca8Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO CampusDepartment of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO CampusDepartment of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO CampusDepartment of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO CampusCenter for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Division of Otolaryngology Head & Neck Surgery, IEO, European Institute of Oncology IRCCSDivision of Otolaryngology Head & Neck Surgery, IEO, European Institute of Oncology IRCCSDepartment of Experimental Oncology, IEO, European Institute of Oncology IRCCS, IEO CampusAbstract Autophagy is important for the removal, degradation and recycling of damaged organelles, proteins, and lipids through the degradative action of lysosomes. In addition to its catabolic function, autophagy is important in cancer and viral-mediated tumorigenesis, including Human Papillomavirus (HPV) positive cancers. HPV infection is a major risk factor in a subset of head and neck cancer (HNC), for which no targeted therapies are currently available. Herein, we assessed autophagy function in HPV-positive HNC. We showed that HPV-positive HNC cells presented a transcriptional and functional impairment of the autophagic process compared to HPV-negative cells, which were reactivated by knocking down HPV E6/E7 oncoproteins, the drivers of cellular transformation. We found that the oncoprotein c-MYC was stabilized and triggered in HPV-positive cell lines. This resulted in the reduced binding of the MiT/TFE transcription factors to their autophagy targets due to c-MYC competition. Thus, the knock-down of c-MYC induced the upregulation of autophagic and lysosomal genes in HPV-positive HNC cells, as well as the increase of autophagic markers at the protein level. Moreover, HPV oncoprotein E7 upregulated the expression of the phosphatase inhibitor CIP2A, accounting for c-MYC upregulation and stability in HPV+ HNC cells. CIP2A mRNA expression negatively correlated with autophagy gene expression in tumor tissues from HNC patients, showing, for the first time, its implication in a transcriptional autophagic context. Both CIP2A and c-MYC knock-down, as well as pharmacological downregulation of c-MYC, resulted in increased resistance to cisplatin treatment. Our results not only show a novel way by which HPV oncoproteins manipulate the host machinery but also provide more insights into the role of autophagy in chemoresistance, with possible implications for targeted HPV-positive HNC therapy.https://doi.org/10.1038/s41419-023-06248-3 |
| spellingShingle | Alessandro Medda Micaela Compagnoni Giorgio Spini Simona Citro Ottavio Croci Stefano Campaner Marta Tagliabue Mohssen Ansarin Susanna Chiocca c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer Cell Death and Disease |
| title | c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer |
| title_full | c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer |
| title_fullStr | c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer |
| title_full_unstemmed | c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer |
| title_short | c-MYC-dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in HPV-positive head and neck cancer |
| title_sort | c myc dependent transcriptional inhibition of autophagy is implicated in cisplatin sensitivity in hpv positive head and neck cancer |
| url | https://doi.org/10.1038/s41419-023-06248-3 |
| work_keys_str_mv | AT alessandromedda cmycdependenttranscriptionalinhibitionofautophagyisimplicatedincisplatinsensitivityinhpvpositiveheadandneckcancer AT micaelacompagnoni cmycdependenttranscriptionalinhibitionofautophagyisimplicatedincisplatinsensitivityinhpvpositiveheadandneckcancer AT giorgiospini cmycdependenttranscriptionalinhibitionofautophagyisimplicatedincisplatinsensitivityinhpvpositiveheadandneckcancer AT simonacitro cmycdependenttranscriptionalinhibitionofautophagyisimplicatedincisplatinsensitivityinhpvpositiveheadandneckcancer AT ottaviocroci cmycdependenttranscriptionalinhibitionofautophagyisimplicatedincisplatinsensitivityinhpvpositiveheadandneckcancer AT stefanocampaner cmycdependenttranscriptionalinhibitionofautophagyisimplicatedincisplatinsensitivityinhpvpositiveheadandneckcancer AT martatagliabue cmycdependenttranscriptionalinhibitionofautophagyisimplicatedincisplatinsensitivityinhpvpositiveheadandneckcancer AT mohssenansarin cmycdependenttranscriptionalinhibitionofautophagyisimplicatedincisplatinsensitivityinhpvpositiveheadandneckcancer AT susannachiocca cmycdependenttranscriptionalinhibitionofautophagyisimplicatedincisplatinsensitivityinhpvpositiveheadandneckcancer |