PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Ganci, Federica; Pulito, Claudio; Valsoni, Sara; Sacconi, Andrea; Turco, Chiara; Vahabi, Mahrou; Manciocco, Valentina; Mazza, Emilia Maria Cristina; Meens, Jalna; Karamboulas, Christina; Nichols, Anthony C.; Covello, Renato; Pellini, Raul; Spriano, Giuseppe; Sanguineti, Giuseppe; Muti, Paola; Bicciato, Silvio; Ailles, Laurie; Strano, Sabrina; Fontemaggi, Giulia; Blandino, Giovanni

doi:10.1158/1078-0432.ccr-19-2485

Cited by 39 publications

(57 citation statements)

References 58 publications

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“…Indeed, we found that depletion of mutant p53 proteins in HNSCC cell lines increased TMPRSS2 expression, suggesting that mutant p53 contributes either directly or indirectly to reduced TMPRSS2 expression. Unlike depletion of mutant p53, silencing of YAP and MYC, two oncogenic co-factors of gain of function mutant p53 proteins did not have any effect of TMPRSS2 expression [22,29,30]. While these ndings may entirely rule out a possibility that gain of function mutant p53-dependent transcriptional networks controls TMPRSS2 expression in HNSCC cells, our observations highlight that tumor cells carrying TP53 mutations may activate post-transcriptional events affecting TMPRSS2 expression.…”

Section: Discussioncontrasting

confidence: 52%

“…Notably, we found that reduced expression of TMPRSS2 associates with HPV negative status and TP53 mutations, both of which are important determinants of poor survival in HNSCC patients. We have recently shown that MYC as oncogenic protein di per se and a MYC-dependent gene signature cooperate with gain of function TP53 mutations to foster HNSCC proliferation and to increase resistance to the treatment [22]. Indeed, we found that depletion of mutant p53 proteins in HNSCC cell lines increased TMPRSS2 expression, suggesting that mutant p53 contributes either directly or indirectly to reduced TMPRSS2 expression.…”

Section: Discussionmentioning

confidence: 77%

“…We have recently reported that MYC is a pivotal mediator of gain of function mutant p53 signalling in HNSCC [22]. We have identi ed a mutantp53/MYC dependent signature whose aberrant activation (high expression levels) associated with shorter overall survival in HNSCC patients (Suppl.…”

Section: Ace2 and Tmprss2 Expression In Hnscc Patientsmentioning

confidence: 99%

“…We have identi ed a mutantp53/MYC dependent signature whose aberrant activation (high expression levels) associated with shorter overall survival in HNSCC patients (Suppl. Figure 3a) [22].…”

Section: Ace2 and Tmprss2 Expression In Hnscc Patientsmentioning

confidence: 99%

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TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

Sacconi¹,

Donzelli²,

Pulito³

et al. 2020

Preprint

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Background: SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas.Methods: The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC.Results: TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation.Conclusions: Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 77%

Section: Ace2 and Tmprss2 Expression In Hnscc Patientsmentioning

confidence: 99%

Section: Ace2 and Tmprss2 Expression In Hnscc Patientsmentioning

confidence: 99%

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TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

Sacconi¹,

Donzelli²,

Pulito³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have recently reported that MYC is a pivotal mediator of gain of function mutant p53 signalling in HNSCC [ 24 ]. We have identified a mutantp53/MYC dependent signature whose aberrant activation (high expression levels) associated with shorter overall survival in HNSCC patients (Suppl.…”

Section: Resultsmentioning

confidence: 99%

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients

Sacconi¹,

Donzelli²,

Pulito³

et al. 2020

J Exp Clin Cancer Res

Self Cite

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Background SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas. Methods The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC. Results TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation. Conclusions Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.

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Revisiting the chaperonin T‐complex protein‐1 ring complex in human health and disease: A proteostasis modulator and beyond

Zeng,

Han,

Pan

et al. 2024

Clinical & Translational Med

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BackgroundDisrupted protein homeostasis (proteostasis) has been demonstrated to facilitate the progression of various diseases. The cytosolic T‐complex protein‐1 ring complex (TRiC/CCT) was discovered to be a critical player in orchestrating proteostasis by folding eukaryotic proteins, guiding intracellular localisation and suppressing protein aggregation. Intensive investigations of TRiC/CCT in different fields have improved the understanding of its role and molecular mechanism in multiple physiological and pathological processes.Main bodyIn this review, we embark on a journey through the dynamic protein folding cycle of TRiC/CCT, unraveling the intricate mechanisms of its substrate selection, recognition, and intriguing folding and assembly processes. In addition to discussing the critical role of TRiC/CCT in maintaining proteostasis, we detail its involvement in cell cycle regulation, apoptosis, autophagy, metabolic control, adaptive immunity and signal transduction processes. Furthermore, we meticulously catalogue a compendium of TRiC‐associated diseases, such as neuropathies, cardiovascular diseases and various malignancies. Specifically, we report the roles and molecular mechanisms of TRiC/CCT in regulating cancer formation and progression. Finally, we discuss unresolved issues in TRiC/CCT research, highlighting the efforts required for translation to clinical applications, such as diagnosis and treatment.ConclusionThis review aims to provide a comprehensive view of TRiC/CCT for researchers to inspire further investigations and explorations of potential translational possibilities.

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PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma

Cited by 39 publications

References 58 publications

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients

Revisiting the chaperonin T‐complex protein‐1 ring complex in human health and disease: A proteostasis modulator and beyond

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