SET protein accumulation prevents cell death in head and neck squamous cell carcinoma through regulation of redox state and autophagy

Ouchida, Amanda Tomie; Uyemura, Valéria Tudella; Queiroz, André Lima; Brauer, Verônica Soares; Cavalcanti-Neto, Marinaldo Pacífico; Sousa, Lucas Oliveira; Uyemura, Sérgio Akira; Curti, Carlos; Leopoldino, Andréia Machado

doi:10.1016/j.bbamcr.2019.01.005

Cited by 12 publications

(4 citation statements)

References 75 publications

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“…In our study, ATG12 expression was independently correlated with poor prognosis. Silencing of ATG12 in HNSCC cells resulted in increased cell death (Ouchida et al, 2019), implying that the ATG12 gene assists cancer cell proliferation by inducing autophagy instead of apoptosis. Our finding that ATG12 is overexpressed in HNSCC implicates its role in cancer and autophagy and presents a novel therapeutic target for HNSCC.…”

Section: Discussionmentioning

confidence: 99%

FKBP1A upregulation correlates with poor prognosis and increased metastatic potential of HNSCC

Patel

Dabhi

Dmello

et al. 2021

Cell Biology International

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy globally. The etiology of HNSCC is multifactorial, including cellular stress induced by a tobacco smoking, tobacco chewing excess alcohol consumption, and human papillomavirus infection. The induction of stress includes autophagy as one of the response pathways in maintaining homeostatic equilibrium. We evaluated the expression of autophagy‐related genes in HNSCC tissues from RNA sequencing datasets and identified 19 genes correlated with poor prognosis and 18 genes correlated with improved prognosis of HNSCC patients. Further analysis of independent gene expression datasets revealed that ATG12, HSP90AB1, and FKBP1A are overexpressed in HNSCC and correlate with poor prognosis, whereas the overexpression of ANXA1, FOS, and ULK3 correlates with improved prognosis. Using independent datasets, we also found that ATG12, HSP90AB1, and FKBP1A expression increased with an increase in the T‐stage of HNSCC. Among all the datasets analyzed, FKBP1A was overexpressed in HNSCC and was strongly associated with lymph node metastasis in multiple in silico datasets. In conclusion, our analysis indicates dynamic alterations in autophagy genes during HNSCC and warrants further investigation, specifically on FKBP1A and its role in tumor progression and metastasis.

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Section: Discussionmentioning

confidence: 99%

FKBP1A upregulation correlates with poor prognosis and increased metastatic potential of HNSCC

Patel

Dabhi

Dmello

et al. 2021

Cell Biology International

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“…In HNSCC, PP2A inactivation largely occurs in a non-genomic way, by overexpression of specific cellular PP2A inhibitors [22][23][24][25][26][27]. Like that, overexpression of CIP2A (Cancerous inhibitor of PP2A) or SET (Suvar/Enhancer of zeste/Trithorax) correlates with poor patient survival, enhanced HNSCC cell survival and decreased cisplatin response [25,[28][29][30][31][32][33]. However, whether other PP2A inactivating mechanisms could be of clinical relevance in HNSCC etiology or therapy response, remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer

Cokelaere,

Dok,

Cortesi

et al. 2023

Cell Oncol.

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PurposeTIPRL1 (target of rapamycin signaling pathway regulator-like 1) is a known interactor and inhibitor of protein phosphatases PP2A, PP4 and PP6 -all pleiotropic modulators of the DNA Damage Response (DDR). Here, we investigated the role of TIPRL1 in the radiotherapy (RT) response of Head and Neck Squamous Cell Carcinoma (HNSCC). MethodsTIPRL1 mRNA (cBioportal) and protein expression (immunohistochemistry) in HNSCC samples were linked with clinical patient data. TIPRL1-depleted HNSCC cells were generated by CRISPR/Cas9 editing, and effects on colony growth, micronuclei formation (microscopy), cell cycle (flow cytometry), DDR signaling (immunoblots) and proteome (mass spectrometry) following RT were assessed. Mass spectrometry was used for TIPRL1 phosphorylation and interactomics analysis in irradiated cells. ResultsTIPRL1 expression was increased in tumor versus non-tumor tissue, with high tumoral TIPRL1 expression associating with lower locoregional control and decreased survival of RT-treated patients. TIPRL1 deletion in HNSCC cells resulted in increased RT sensitivity, a faster but prolonged cell cycle arrest, increased micronuclei formation and an altered proteome-wide DDR. Upon irradiation, ATM phosphorylates TIPRL1 at Ser265. A nonphospho Ser265Ala mutant could not rescue the increased radiosensitivity phenotype of TIPRL1-depleted cells. While binding to PP2A-like phosphatases was confirmed, DNA-dependent protein kinase (DNA-PKcs), RAD51 recombinase and nucleosomal histones were identified as novel TIPRL1 interactors. Histone binding, although stimulated by RT, was adversely affected by TIPRL1 Ser265 phosphorylation. ConclusionsOur findings underscore a clinically relevant role for TIPRL1 and its ATM-dependent phosphorylation in RT resistance through modulation of the DDR, highlighting its potential as a new HNSCC predictive marker and therapeutic target.

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“…In HNSCC, PP2A inactivation largely occurs in a non-genomic way, by overexpression of specific cellular PP2A inhibitors (Gouttia et al, 2022;Junttila et al, 2007;Katz et al, 2010;Leopoldino et al, 2012;Patel et al, 2008;Ventelä et al, 2014). Like that, overexpression of CIP2A (Cancerous inhibitor of PP2A) or SET (Suvar/Enhancer of zeste/Trithorax) correlates with poor patient survival, enhanced HNSCC cell survival and decreased cisplatin response (Alzahrani et al, 2020;Böckelman et al, 2011;Leopoldino et al, 2012;Liu et al, 2014;Ouchida et al, 2019;Routila et al, 2016;Sobral et al, 2014). However, whether other PP2A inactivating mechanisms could be of clinical relevance in HNSCC etiology or therapy response, remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer

Cokelaere,

Dok,

Cortesi

et al. 2023

Preprint

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TIPRL1 (target of rapamycin signaling pathway regulator-like 1) is a known interactor and inhibitor of protein phosphatases PP2A, PP4 and PP6 – all pleiotropic modulators of the DNA Damage Response (DDR). Here, we describe a new role for TIPRL1 in the radiotherapy (RT) response of Head and Neck Squamous Cell Carcinoma (HNSCC). TIPRL1 expression was found increased in tumor versus non- tumor tissue, with high tumoral TIPRL1 expression associating with lower locoregional control and decreased survival of RT-treated patients. TIPRL1 deletion in HNSCC cells resulted in increased RT sensitivity, a faster but prolonged cell cycle arrest, increased micronuclei formation and an altered proteome-wide DDR. Upon irradiation, ATM phosphorylates TIPRL1 at Ser265, contributing to TIPRL1-mediated RT resistance. Mass spectrometry analysis identified DNA-PKcs, RAD51 and nucleosomal histones as novel TIPRL1 interactors. Histone binding, although stimulated by RT, was adversely affected by TIPRL1 Ser265 phosphorylation. Our findings underscore a clinically relevant role for TIPRL1 and its ATM-dependent phosphorylation in RT resistance through modulation of DNA damage checkpoint activation and repair.

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SET protein accumulation prevents cell death in head and neck squamous cell carcinoma through regulation of redox state and autophagy

Cited by 12 publications

References 75 publications

FKBP1A upregulation correlates with poor prognosis and increased metastatic potential of HNSCC

FKBP1A upregulation correlates with poor prognosis and increased metastatic potential of HNSCC

TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer

TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer

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