High expression of transcriptional coactivator p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma

Abstract

BackgroundIt has been suggested that p300 participates in the regulation of a wide range of cell biological processes and mutation of p300 has been identified in certain types of human cancers. However, the expression dynamics of p300 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear.MethodsIn this study, the methods of reverse transcription-polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry (IHC) were utilized to investigate protein/mRNA expression of p300 in HCCs. Receiver operating characteristic (ROC) curve analysis, spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data.ResultsUp-regulated expression of p300 mRNA and protein was observed in the majority of HCCs by RT-PCR and Western blotting, when compared with their adjacent non-malignant liver tissues. According to the ROC curves, the cutoff score for p300 high expression was defined when more than 60% of the tumor cells were positively stained. High expression of p300 was examined in 60/123 (48.8%) of HCCs and in 8/123 (6.5%) of adjacent non-malignant liver tissues. High expression of p300 was correlated with higher AFP level, larger tumor size, multiplicity, poorer differentiation and later stage (P < 0.05). In univariate survival analysis, a significant association between overexpression of p300 and shortened patients' survival was found (P = 0.001). In different subsets of HCC patients, p300 expression was also a prognostic indicator in patients with stage II (P = 0.007) and stage III (P = 0.011). Importantly, p300 expression was evaluated as an independent prognostic factor in multivariate analysis (P = 0.021). Consequently, a new clinicopathologic prognostic model with three poor prognostic factors (p300 expression, AFP level and vascular invasion) was constructed. The model could significantly stratify risk (low, intermediate and high) for overall survival (P < 0.0001).ConclusionsOur findings provide a basis for the concept that high expression of p300 in HCC may be important in the acquisition of an aggressive phenotype, suggesting that p300 overexpression, as examined by IHC, is an independent biomarker for poor prognosis of patients with HCC. The combined clinicopathologic prognostic model may become a useful tool for identifying HCC patients with different clinical outcomes.

High expression of p300 in human breast cancer correlates with tumor recurrence and predicts adverse prognosis

“…A role for p300 in tumor suppression has been proposed by the evidence that disturbance of p300 function by viral oncoproteins is essential for the transformation of rodent primary cells [9,10] . However, several studies revealed that transcriptional coactivator p300 is a positive regulator of cancer progression and related to tumorigenesis of various human cancers [11][12][13] . It has been suggested that the cooperation between CtBP1 and p300 appears to be central in discriminating nuclear receptor repression versus stimulation of genes at early times after hormone exposure in breast cancer cells [14].…”

p300 Regulates Liver Functions by Controlling p53 and C/EBP Family Proteins through Multiple Signaling Pathways

“…High-level expression of p300 is associated with poor prognoses and epithelial-to-mesenchymal transition in HCC (14,15). p300 forms complexes with C/EBP proteins and activates promoters of genes involved in triglyceride synthesis during the development of hepatic steatosis (9).…”

The multifaceted role of lysine acetylation in cancer: prognostic biomarker and therapeutic target

“…In this context, loss of heterozygosity (LOH) at the p300 locus has been observed in numerous cancers, including hepatocellular, colorectal, oral, breast, ovarian, gastric carcinomas and glioblastomas [11]. Consistently, several studies have also shown that loss of p300 correlates with aggressive features and poor prognosis of hepatocellular carcinoma (HCC) [12, 13], breast cancer [14], cutaneous squamous cell carcinoma (SCC) [15] and nasopharyngeal carcinoma [16]. However, p300 is also found to be overexpressed in prostate cancer, where it regulates fatty acid synthase expression, lipid metabolism and prostate cancer growth [5, 17, 18].…”