Decreased Expression of Nuclear p300 Is Associated with Disease Progression and Worse Prognosis of Melanoma Patients

Abstract

BackgroundGenomic instability due to UV radiation is one of the leading causes for melanoma. Histone acetyltransferase p300 plays an indispensible role in DNA repair and maintenance of genomic integrity. The present study was performed to analyze the correlation between p300 expression, melanoma progression and patient survival.MethodsTissue microarray and immunohistochemical analysis was employed to study the expression of p300 in melanoma patients. A total of 358 melanoma patients (250 primary melanoma and 108 metastatic melanoma) were used for the study. Kaplan-Meier, univariate and multivariate Cox regression analysis, and receiver-operating characteristic curves, were used to elucidate the prognostic significance of p300 expression.ResultsOur results demonstrate that p300 is expressed in both nucleus and cytoplasm but the nuclear expression of p300 is predominant. The progression of disease from dysplastic nevi to primary melanoma and to metastatic melanoma was associated with decreased nuclear and increased cytoplasmic p300 expression. Especially, the loss of nuclear and gain in cytoplasmic p300 was correlated with the progression of melanoma from AJCC stage II to stage III, which requires the migration and metastasis of cancer cells from primary sites to lymph nodes. Similarly, decrease in nuclear, and increase in cytoplasmic p300 expression correlated with worse survival of melanoma patients. Nuclear p300 but not cytoplasmic p300 could predict the patient survival independent of AJCC stage, age and gender.ConclusionLoss of nuclear p300 expression is an indicator of worse patient survival and is an independent prognostic marker for melanoma.

A combination of p300 and Braf expression in the diagnosis and prognosis of melanoma

“…Data from our previous study showed that though cytoplasmic p300 expression was significantly associated with clinico-pathologic characteristics of melanoma, only nuclear p300 had prognostic significance [10]. Even in the present study, cytoplasmic p300 expression was only informative during the diagnosis part of the analysis but was not a significant prognostic factor (Table  4).…”

“…Furthermore, we also found that nuclear p300 expression was an independent prognostic factor, suggesting the importance of targeting the functions of histone acetyltransferases (HAT) in melanoma therapy [10]. Stability and activity of p300 protein have been shown to be regulated by phosphorylation, and phosphorylation of p300 by mitogen activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK1/2) has been reported to promote the degradation of p300 protein [11,12].…”

132 Eyes absent gene (EYA1) is a pathogenic driver and a therapeutic target for melanoma

“…The selection of melanoma tissue blocks and construction of tumor tissue microarrays have been described previously [6,7,12,[33][34][35][36][37]. The formalinfixed, paraffin embedded archival biopsies of benign melanocytic nevi, melanoma in situ, invasive primary melanoma and metastatic melanoma were obtained from the 1990 to 2009 archives from the Department of Pathology at Vancouver General Hospital, Vancouver, Canada.…”

“…The clinicopathological data was available for all melanoma cases. EYA1 expression was analyzed by immunohistochemistry on paraffin-embedded tissue microarrays as described previously [6,7,12,[33][34][35][36][37]. Briefly, de-paraffinized 4μm tissue sections were treated 30 minutes in 0.1M sodium citrate (PH6.0) at 95˚C for antigen retrieval.…”

“…A previously described [6,7,12,[33][34][35][36][37]] a 4-point scoring system was used to determine intensity of EYA1 staining. Scoring was performed by three independent scorers, including a dermatopathologist, without access to clinico-pathological information of the sections.…”