Background: HNSCC is a heterogeneous group of tumors caused mainly by environmental factors and human papillomavirus (HPV) infections. HPV- and HPV+ HNSCC are considered distinct entities, however, they are still treated with the same therapeutic strategies. HPV-induced tumorigenesis is mainly mediated by the E6/E7 oncoviral proteins, that, among all, alter the epigenetics of the host cells. Nevertheless, epigenetic profiles of HNSCC subtypes have not been clearly profiled. Results and Conclusion: hPTMs super-SILAC analysis of HNSCC cell lines and patients’ tissue samples revealed significant differences in the enrichment levels of some hPTM in HPV+ samples compared to HPV- ones and in tumoral tissues compared to normal ones. We focused on one of these identified hPTM and demonstrated that its levels are regulated by E6 and E7. We identified a histone modifier responsible for this hPTM whose levels are upregulated by E6/E7 and are higher in HPV+ compared to HPV- HNSCC cell lines and patients’ tissue samples, as is for the related hPTM. Silencing this enzyme through shRNA in HNSCC cell lines reduced proliferation and migration rates in both subtypes. It also downregulates the expression levels of some EMT mesenchymal makers and of a crucial oncogene involved in HNSCC. RNA-seq analysis revealed that other programs are instead specifically regulated according to the subtype: immune-response related genes are mainly activated in HPV- cell lines, while genes involved in cell differentiation in the HPV+ ones. Our research paves the way to novel lines of research and identifies a promising novel epigenetic target for HNSCC treatments.

THE HISTONE POST-TRANSLATIONAL MODIFICATION LANDSCAPE IN HPV+ AND HPV- HEAD AND NECK SQUAMOUS CELL CARCINOMA: CHARACTERIZING THE ONCOGENIC ROLE OF THE H3K36ME2 METHYLTRANSFERASE NSD2 / L. Ghiani ; tutor: S. Chiocca ; co-tutor: M.Alcalay ; internal advisor: S. Minucci ; external advisor: G.P. Dotto ; phd coordinator: G. Viale. - : . Dipartimento di Oncologia ed Emato-Oncologia, 2021 Mar 30. ((32. ciclo, Anno Accademico 2020.

THE HISTONE POST-TRANSLATIONAL MODIFICATION LANDSCAPE IN HPV+ AND HPV- HEAD AND NECK SQUAMOUS CELL CARCINOMA: CHARACTERIZING THE ONCOGENIC ROLE OF THE H3K36ME2 METHYLTRANSFERASE NSD2

L. Ghiani
2021

Abstract

Background: HNSCC is a heterogeneous group of tumors caused mainly by environmental factors and human papillomavirus (HPV) infections. HPV- and HPV+ HNSCC are considered distinct entities, however, they are still treated with the same therapeutic strategies. HPV-induced tumorigenesis is mainly mediated by the E6/E7 oncoviral proteins, that, among all, alter the epigenetics of the host cells. Nevertheless, epigenetic profiles of HNSCC subtypes have not been clearly profiled. Results and Conclusion: hPTMs super-SILAC analysis of HNSCC cell lines and patients’ tissue samples revealed significant differences in the enrichment levels of some hPTM in HPV+ samples compared to HPV- ones and in tumoral tissues compared to normal ones. We focused on one of these identified hPTM and demonstrated that its levels are regulated by E6 and E7. We identified a histone modifier responsible for this hPTM whose levels are upregulated by E6/E7 and are higher in HPV+ compared to HPV- HNSCC cell lines and patients’ tissue samples, as is for the related hPTM. Silencing this enzyme through shRNA in HNSCC cell lines reduced proliferation and migration rates in both subtypes. It also downregulates the expression levels of some EMT mesenchymal makers and of a crucial oncogene involved in HNSCC. RNA-seq analysis revealed that other programs are instead specifically regulated according to the subtype: immune-response related genes are mainly activated in HPV- cell lines, while genes involved in cell differentiation in the HPV+ ones. Our research paves the way to novel lines of research and identifies a promising novel epigenetic target for HNSCC treatments.
CHIOCCA, SUSANNA
VIALE, GIUSEPPE
Head and Neck Suqamous Cell Carcinoma (HNSCC); Human Papillomavirus (HPV); epigenetics; histone post-translational modifications (hPTMs); histone methyltransferase; oncogenic pathways
Settore BIO/11 - Biologia Molecolare
THE HISTONE POST-TRANSLATIONAL MODIFICATION LANDSCAPE IN HPV+ AND HPV- HEAD AND NECK SQUAMOUS CELL CARCINOMA: CHARACTERIZING THE ONCOGENIC ROLE OF THE H3K36ME2 METHYLTRANSFERASE NSD2 / L. Ghiani ; tutor: S. Chiocca ; co-tutor: M.Alcalay ; internal advisor: S. Minucci ; external advisor: G.P. Dotto ; phd coordinator: G. Viale. - : . Dipartimento di Oncologia ed Emato-Oncologia, 2021 Mar 30. ((32. ciclo, Anno Accademico 2020.
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/820678
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