Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets.

The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients.

KH-like Domains in PARP9/DTX3L and PARP14 Coordinate Protein-Protein Interactions to Promote Cancer Cell Survival.

Certain members of the ADP-ribosyltransferase superfamily (ARTD or PARP enzymes) catalyse ADP-ribosylation in response to cellular stress, DNA damage and viral infection and are upregulated in various tumours. PARP9, its binding partner DTX3L and PARP14 protein levels are significantly correlated in head and neck squamous cell carcinoma (HNSCC) and other tumour types though a mechanism where PARP9/DTX3L regulates PARP14 post-transcriptionally. Depleting PARP9, DTX3L or PARP14 expression in HNSCC or HeLa cell lines decreases cell survival through a reduction of proliferation and an increase in apoptosis. A partial rescue of survival was achieved by expressing a PARP14 truncation containing a predicted eukaryotic type I KH domain. KH-like domains were also found in PARP9 and in DTX3L and contributed to protein-protein interactions between PARP9-DTX3L and PARP14-DTX3L. Homodimerization of DTX3L was also coordinated by a KH-like domain and was disrupted by site-specific mutation. Although, cell survival promoted by PARP14 did not require ADP-ribosyltransferase activity, interaction of DTX3L in vitro suppressed PARP14 auto-ADP-ribosylation and promoted trans-ADP-ribosylation of PARP9 and DTX3L. In summary, we characterised PARP9-DTX3L-PARP14 interactions important to pro-survival signalling in HNSCC cells, albeit in PARP14 catalytically independent fashion.

Carcinogênese de cabeça e pescoço: impacto do polimorfismo MTHFD1 G1958A / Head and neck carconogenesis: impact of MTHFD1 G1958A polymorphism

OBJETIVO: Investigar o polimorfismo MTHFD1 G1958A envolvido no metabolismo do folato no risco para o câncer de cabeça e pescoço e verificar a associação entre esse polimorfismo com fatores de risco e características clínico-histopatológicas. MÉTODOS: Estudo retrospectivo que avaliou o polimorfismo MTHFD1 G1958A em 694 indivíduos (240 pacientes e 454 controles), por meio da técnica de análise de polimorfismo de comprimento de fragmento de restrição. Para análise estatística foram utilizados os testes de regressão logística múltipla e qui-quadrado. RESULTADOS: Tabagismo e idade superior a 42 anos foram preditores da doença (p < 0,05). Os genótipos MTHFD1 1958GA ou AA foram associados ao tabagismo (p = 0,04) e etilismo (p = 0,03) e estão presentes em maior proporção em tumores com estádios mais avançados (p = 0,04) e em pacientes com menor sobrevida (p = 0,03). CONCLUSÃO: A presença do polimorfismo MTHFD1 G1958A associada aos hábitos tabagista e etilista aumenta o risco para desenvolvimento de câncer de cabeça e pescoço.

OBJECTIVE: To investigate the MTHFD1 G1958A polymorphism involved in the folate metabolism as a risk for head and neck cancer, and to find the association of the polymorphism with the risk factors and clinical and histopathological characteristics. METHODS: Retrospective study investigating MTHFD1 G1958A polymorphism in 694 subjects (240 patients in the Case Group and 454 in the Control Group) by Restriction Fragment Length Polymorphism (RFLP) Analysis. Multiple logistic regression and chi-square tests were used in the statistical analysis. RESULTS: Multivariable analysis showed that smoking and age over 42 years were disease predictors (p < 0.05). MTHFD1 1958GA or AA genotypes were associated with smoking (p = 0.04) and alcoholism (p = 0.03) and were more often found in more advanced stage tumors (p = 0.04) and in patients with a shorter survival (p = 0.03). CONCLUSION: The presence of MTHFD1 G1948A polymorphism associated with smoking and alcoholism raises the head and neck cancer risk.

5-Methyltetrahydrofolate-homocysteine methyltransferase gene polymorphism (MTR) and risk of head and neck cancer

The functional effect of the A>G transition at position 2756 on the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase), involved in folate metabolism, may be a risk factor for head and neck squamous cell carcinoma (HNSCC). The frequency of MTR A2756G (rs1805087) polymorphism was compared between HNSCC patients and individuals without history of neoplasias. The association of this polymorphism with clinical histopathological parameters was evaluated. A total of 705 individuals were included in the study. The polymerase chain reaction-restriction fragment length polymorphism technique was used to genotype the polymorphism. For statistical analysis, the chi-square test (univariate analysis) was used for comparisons between groups and multiple logistic regression (multivariate analysis) was used for interactions between the polymorphism and risk factors and clinical histopathological parameters. Using univariate analysis, the results did not show significant differences in allelic or genotypic distributions. Multivariable analysis showed that tobacco and alcohol consumption (P < 0.05), AG genotype (P = 0.019) and G allele (P = 0.028) may be predictors of the disease and a higher frequency of the G polymorphic allele was detected in men with HNSCC compared to male controls (P = 0.008). The analysis of polymorphism regarding clinical histopathological parameters did not show any association with the primary site, aggressiveness, lymph node involvement or extension of the tumor. In conclusion, our data provide evidence that supports an association between the polymorphism and the risk of HNSCC.

Change of telomerase activity in peripheral whole blood of head and neck squamous cell carcinoma patients before and after surgery: a pilot study

BACKGROUND The purpose of this study was to evaluate telomerase activity in peripheral whole blood from head and neck squamous cell carcinoma (HNSCC) patients as a biomarker for diagnosis of HNSCC or detection of recurrence during follow-up. MATERIALS AND METHODS Telomerase activity was measured from peripheral whole blood extracts by telomerase repeat amplification protocol (TRAP) in HNSCC patients before and after surgery and in a control group. Sixty-two HNSCC patients and 42 control subjects were included. RESULTS Telomerase activity was found in 41 out of 62 (66.1%) HNSCC patients before surgery and in 8 out of 42 (19.0%) controls (p<0.001). Among 41 HNSCC patients who showed positive telomerase activity before surgery, 32 (78.1%) showed a conversion of telomerase activity to negative after surgery. In follow-up, 6 out of 8 (75%) showed conversion of telomerase activity from negative to positive after recurrence. Telomerase activity was changed to negative in 4 out of 6 (66%) recurred patients with positive telomerase activity after second surgery. CONCLUSION The telomerase activity in peripheral whole blood extracts of HNSCC patients might be a useful biomarker for detecting recurrence after treatment. Further study with larger sample size using a more sensitive detection method of telomerase activity is necessary to verify these results (AU)

Polimorfismos GSTT1 e GSTM1 em indivíduos tabagistas com carcinoma espinocelular de cabeça e pescoço / GSTT1 and GSTM1 polymorphism in cigarette smokers with head and neck squamous cell carcinoma

A variabilidade em genes relacionados aos processos de ativação e detoxificação de carcinógenos pode interferir na suscetibilidade ao câncer. OBJETIVO: Investigar a relação entre os polimorfismos GSTT1 e GSTM1 nulos e o risco para o carcinoma espinocelular de cabeça e pescoço em indivíduos tabagistas. MATERIAL E MÉTODO: Este estudo caso-controle foi realizado na Faculdade de Medicina de São José do Rio Preto, Brasil. Foram avaliadas as freqüências dos genótipos nulos GSTT1 e GSTM1 por PCR multiplex em 60 pacientes com carcinoma espinocelular de cabeça e pescoço e 60 indivíduos sem a doença. RESULTADOS: A cavidade oral foi o sítio de tumor mais freqüente. O genótipo GSTT1 nulo foi encontrado em 33,3 por cento dos pacientes e em 23,3 por cento dos indivíduos controles (p=0,311). Os grupos caso e controle apresentaram freqüências do genótipo GSTM1 nulo de 35 por cento e 48,3 por cento, respectivamente (p=0,582). Não foram encontradas associações entre o hábito etilista e genótipos nulos GSTT1 e GSTM1 em ambos os grupos (valores de p>0,05). O gênero masculino e o hábito etilista foram prevalentes em ambos os grupos. CONCLUSÃO: Neste estudo não foi possível estabelecer uma correlação entre os genótipos nulos GSTT1 e GSTM1 e o carcinoma espinocelular de cabeça e pescoço em indivíduos tabagistas.

Gene variability related to carcinogen activation and detoxification may interfere with susceptibility to head and neck cancer. AIM: To investigate the relation between GSTT1 and GSTM1 null polymorphisms and the risk of head and neck squamous cell carcinoma in cigarette smokers. MATERIAL AND METHOD: A case-control study conducted at the Sao Jose do Rio Preto Medical School, Brazil. GSTM1 and GSTT1 null genotype frequencies were evaluated by multiplex PCR in 45 cigarette smokers with head and neck squamous cell carcinomas and 45 cigarette smokers without this disease. RESULTS: The oral cavity was the most prevalent tumor site for squamous cell carcinoma. The GSTT1 null genotype was found in 33.3 percent of the Experimental Group and 23.3 percent of the Control Group (p= 0.311). Experimental and Control Groups had GSTM1 null genotype frequencies of 35 percent and 48.3 percent (p=0.582). No association between alcohol consumption and GSTT1 and GSTMI null genotypes was found in these groups (p-values>0.05). There were more men, and alcohol consumption was prevalent in both groups. CONCLUSION: In this study we were unable to show a correlation between GSTM1 and GSTT1 genotypes and the development of head and neck squamous cell carcinomas in cigarette smokers.

O papel das proteínas da matriz extracelular e das metaloproteinases em carcinomas de cabeca e pescoco: uma atualizacão bibliográfica / The role of matrix extracellular proteins and metalloproteinases in head and neck carcinomas: an updated review

Interacões entre células neoplásicas e constituintes da matriz extracelular (MEC) interferem fortemente no desenvolvimento tumoral, incluindo os localizados em cabeca e pescoco, pois influenciam a proliferacão e sobrevivência celular, bem como a sua capacidade de migrar do sítio primário para outros tecidos e formar metástases. Essa migracão celular é facilitada pela destruicão parcial da MEC, a qual é realizada pelas metaloproteinases (MMPs), que representam uma família de mais de vinte endopeptidases, com atividade controlada pela expressão de inibidores específicos (TIMPs). Diversos estudos utilizando-se de marcadores para constituintes da MEC bem como pelas MMPs têm fornecido informacões adicionais sobre o diagnóstico e prognóstico em carcinomas de cabeca e pescoco. Nesta revisão consideraremos o papel da MEC e das MMPs na progressão desses tumores, enfatizando que não somente a degradacão proteolítica está envolvida neste processo, como também interacões entre vários constituintes da MEC fornecem substrato para regulacão e crescimento destes tumores.

Bases genéticas y molecularesde los paragangliomas / Genetic and molecular bases of paragangliomas

Los paragangliomas y feocromocitomas son tumores neuroendocrinos que se desarrollan en la médula extra adrenaly adrenal, respectivamente. Estos tumores aparecen en determinados síndromes familiares, como la neoplasia endocrina múltiple de tipo 1 y tipo 2, la enfermedad de Von Hippel Lindau, la neurofibromatosis de tipo 1 y síndromes paraganglionares familiares. Estos últimos síndromes muestran una asociación muy fuerte con mutaciones en genes del complejo mitocondrial de la succinato deshidrogenasa, como son SDHB, SDHC y SDHD. Este complejo enzimático se relaciona con la aparición de tumores a través de mecanismos implicados en proliferación celular, apoptosis, y alteración de la función sensora de oxígeno, de los cuales ninguno ha podido atribuirse todavía con certeza como causa del desarrollo tumoral. En los últimos años se han realizado varios estudios sobre estos genes en relación con el diagnóstico adecuado de paraganglioma y feocromocitoma, así como con la determinación de mutaciones germinales en los casos familiares y en los esporádicos, y su utilidad en el consejo genético en este grupo de pacientes (AU)

Paragangliomas and pheochromocytomas are neuroendocrine tumors arising in the extra adrenal and adrenalmedulla, respectively. These tumors appear in certain familial syndromes, such as multiple endocrine neoplasia types 1 and 2, Von Hippel Lindau disease, neurofibromatosis type 1 and familial paraganglioma syndromes. The latter syndromes show a strong association with germline mutations of succinate dehydrogenase subunits, such as SDHB, SDHC and SDHD. This enzyme complex is related to tumorigenesis through mechanisms involved in cell proliferation, apoptosis, and alterations in oxygen sensing function, although none of these factors has been clearly identified as a cause of tumoral development. In the last few years, several studies have been performed of these genes in relation to correct diagnosis of paraganglioma and pheochromocytoma, as well as determination of germline mutations in familial and sporadic cases and its utility in genetic counselling in these patients (AU)

Detección mediante RT-PCR de células tumorales circulantes en pacientes con melanoma maligno en estadio III. Correlación con el grosor y la histología del tumor / Detection of circulating tumoral cells by RT-PCR in patients with stage III of malignant melanoma. Correlation with tumor thickness and hystologic type

El objetivo de nuestro estudio ha sido evaluar la utilidad de la Transcriptasa reversa y Reacción en cadena de la polimerasa (RT-PCR) en la detección de la enzima tirosinasa como marcador de la presencia de células derivadas de melanocitos en pacientes con melanoma maligno en estadio III y su correlación con factores pronósticos como el grosor y la forma clínico-histológica del tumor. La detección de células de melanoma circulantes mediante RT-PCR se ha realizado en un grupo de 28 pacientes con melanoma maligno en estadio III (clasificación de la AJCC). Nuestros resultados demuestran una alta positividad de la PCR en este grupo de pacientes siendo más frecuente en tumores con un grosor > 4mm (75 por ciento). No obstante, no encontramos correlación entre la positividad de la PCR y la forma clínico-histológica del tumor. Nuestros resultados sugieren la posibilidad de aplicar la detección del ARNm de la tirosinasa mediante RT-PCR como un nuevo marcador en el pronóstico del melanoma maligno (AU)