High Expression of p300 Has an Unfavorable Impact on Survival in Resectable Esophageal Squamous Cell Carcinoma

doi:10.1016/j.athoracsur.2010.12.012

The Annals of Thoracic Surgery

Volume 91, Issue 5, May 2011, Pages 1531-1538

https://doi.org/10.1016/j.athoracsur.2010.12.012 Get rights and content

Background

p300 is a transcriptional regulator that is involved in fundamental processes such as cell proliferation, cell differentiation, and tumor progression. However, its role and clinical significance in resectable esophageal squamous cell carcinoma (ESCC) has not been elucidated. The purpose of this study was to explore whether there was a correlation between the expression of p300 by immunohistochemistry and the clinical outcome of a group of patients with ESCC treated with surgical resection.

Methods

Tissue microarray that included 240 surgically resected ESCC specimens and 56 cases of paracancerous tissues was successfully generated for immunohistochemical evaluation. The clinical and prognostic significance of p300 expression was analyzed statistically. Kaplan-Meier analysis was used to compare the postoperative survival between groups.

Results

The expression frequency and expression levels of p300 were significantly higher in ESCC specimens (62.5%, 150 of 240) than in normal esophageal mucosa (8.9%, 5 of 56; p < 0.001). Increased p300 expression was associated with higher histologic grade (p = 0.012), T category (p = 0.032), and N category (p = 0.013). Patients with low expression of p300 demonstrated higher overall survival compared with those with high expression of p300 (mean, 80.0 months versus 56.9 months; p < 0.001). A similar result was observed for disease-free survival (mean, 78.3 months versus 53.1 months; p < 0.001). Furthermore, p300 expression could stratify the patient survival (disease-free survival and overall survival) in stage II (p = 0.002, 0.003, respectively). Multivariate analysis showed that the level of p300 expression was an independent prognostic factor in ESCC (relative risk, 1.658; p = 0.017).

Conclusions

High expression of p300 suggests poor prognosis for patients with resectable ESCC.

Section snippets

Patient Selection

This study was approved by the medical ethics committee of Sun Yat-sen University Cancer Center. Two hundred sixty-five primary ESCC patients who underwent surgery at the Department of Thoracic Surgery, Cancer Center, Sun Yat-sen University, between October 2000 and April 2007 were eligible for inclusion in the study. The histologic grade and clinical stage of the tumors were defined according to the seventh edition of the TNM classification of the International Union Against Cancer (2009) [21

Patient Characteristics

Sixty-eight women and 172 men, aged from 32 to 79 years (median, 58.0 years), were included in the study. The clinicopathologic characteristics of the 240 patients are listed in Table 1.

p300 Immunoreactivity Score Cutoff Value

The p300 immunoreactivity score cutoff value was defined by using receiver operating characteristic curve analysis. The value closest to the point with both maximal sensitivity and specificity (ie, the point [0.0, 0.1] on the curve) was selected as the cutoff value. In this study, the result showed that the

Comment

Our results showed that a significant percentage of cells in the normal esophageal mucosa demonstrated positive staining for p300. However, the expression levels of p300 in the ESCC cohort were significant higher compared with those in normal esophageal mucosa. This finding implies that p300 may be useful in the auxiliary diagnosis of ESCC. A further analysis showed that high expression of p300 was closely associated with the clinicopathologic factors related to tumor progression (advanced T

References (28)

H. Shimada et al.
Prediction of survival with squamous cell carcinoma antigen in patients with resectable esophageal squamous cell carcinoma
Surgery
(2003)
S. Kobayashi et al.
The p53 gene mutation is of prognostic value in esophageal squamous cell carcinoma patients in unified stages of curability
Am J Surg
(1999)
M. Ikeguchi et al.
Combined analysis of p53 and retinoblastoma protein expressions in esophageal cancer
Ann Thorac Surg
(2000)
M. Guermah et al.
Synergistic functions of SII and p300 in productive activator-dependent transcription of chromatin templates
Cell
(2006)
M.E. Fermento et al.
Intracellular distribution of p300 and its differential recruitment to aggresomes in breast cancer
Exp Mol Pathol
(2010)
M. Wasner et al.
Cyclin B1 transcription is enhanced by the p300 coactivator and regulated during the cell cycle by a CHR-dependent repression mechanism
FEBS Lett
(2003)
J. Qi et al.
Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors
Cancer Cell
(2010)
A. Jemal et al.
Cancer statistics, 2010
CA Cancer J Clin
(2010)
J. Tepper et al.
Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781
J Clin Oncol
(2008)
P.C. Enzinger et al.
Esophageal cancer
N Engl J Med
(2003)

M. Hoshino et al.

Nuclear expression of phosphorylated EGFR is associated with poor prognosis of patients with esophageal squamous cell carcinoma

Pathobiology

(2007)

M. Dreilich et al.

HER-2 overexpression (3+) in patients with squamous cell esophageal carcinoma correlates with poorer survival

Dis Esophagus

(2006)

J.Y. Hsia et al.

Expression of apoptosis-regulating proteins p53, Bcl-2, and Bax in primary resected esophageal squamous cell carcinoma

Neoplasma

(2001)

M. Torzewski et al.

The prognostic significance of epidermal growth factor receptor expression in squamous cell carcinomas of the oesophagus

Anticancer Res

(1997)

Cited by (44)

Epigenetic modifications and regulations in gastrointestinal diseases
2022, Epigenetics in Organ Specific Disorders
The gastrointestinal tract is the hub for digestion and assimilation of all ingested matters. Any change or disruption in the normal process can severely impact the health of any individual, sometimes even resulting in acute or chronic disease. A basic trait of almost all diseases, including cancer, is a change in genetic and epigenetic machinery. These changes, along with other microenvironmental factors, together mediate the clinical manifestations of any disease.
4-Pyridone-3-carboxylic acid as a benzoic acid bioisostere: Design, synthesis, and evaluation of EP300/CBP histone acetyltransferase inhibitors
2021, Bioorganic and Medicinal Chemistry Letters
Histone acetyltransferases (HATs) play a crucial role in post-translational modification. Among them, overexpression, mutation, or hyperfunction of EP300/CBP has been associated with various cancers. In this study, we identified the novel compound 2-chloro-5-[5-[(E)-[1-(3-chlorophenyl)-3-methyl-5-oxo-pyrazol-4-ylidene]methyl]-2-furyl]benzoic acid (1) as an EP300 HAT inhibitor via virtual screening. Further research has been focused on the design, synthesis, and in vitro biological evaluation of virtual hit derivatives. The studies revealed that 4-pyridone-3-carboxylic acid derivatives exhibited bioisosterism of benzoic acid. Replacement proved effective, providing compounds with similar EP300 HAT-inhibitory activity and improved cell growth-inhibitory activity compared to the benzoic acid analogs. Through these studies, we identified a potent and selective EP300/CBP HAT inhibitor.
HAT inhibitors in cancer therapy
2020, Histone Modifications in Therapy
Acetylation is a posttranslational modification occurring on lysine residues of both histone and nonhistone proteins, and it plays a crucial role in several biological settings. The acetylation reaction is catalyzed by histone acetyltransferases (HATs), and the dysregulation of this enzymatic activity is implicated in many disease conditions such as cancer and inflammatory and neurological disorders. To date, despite the identification of several histone acetyltransferase inhibitors (HATi), there is still the need for more potent, selective, and metabolically stable HATi that may serve as therapeutic agents and/or chemical tools to further advance the elucidation of complex HAT biology. In this chapter, we summarize the main features of HAT enzymes and related diseases, with a particular focus on HATi, and analyze their structure–activity relationships, modes of action, and potential use as anticancer therapeutics.
Structural dynamics and quantum mechanical aspects of shikonin derivatives as CREBBP bromodomain inhibitors
2018, Journal of Molecular Graphics and Modelling
Citation Excerpt :
The architecture of CREBBP protein consists of a HAT domain, a CREB binding domain, several zinc finger domains, a plant homology domain (PHD) and a bromodomain (BRD). Literature revealed that the bromodomain of CREBBP is one of the major considerations in anticancer drug target [16–19], involved several major biological functions like DNA replication and repair, genomic stability, cell cycle regulation and cell growth. Furthermore, various oncology-relevant transcription factors like cMYB, c-MYC and p53 are found to be amended by it [20–24].
The Proteins involved in the chemical modification of lysine residues in histone, is currently being excessively focused as the therapeutic target for the treatment of cell related diseases like cancer. Among these proteins, the epigenetic reader, CREB-binding protein (CREBBP) bromodomain is one of the most prominent targets for effective anticancer drug design, which is responsible for the reorganization of acetylated histone lysine residues. Therefore, this study employed an integrative approach of structure based drug design, in combination with Molecular Dynamics (MD) and QM/MM study to identify as well as to describe the binding mechanism of two shikonin derivatives, acetylshikonin and propionylshikonin as inhibitors of CREBBP bromodomain. Here induced fit docking strategy was employed to explore the important intrinsic interactions of ligands with CREBBP bromodomain, consistently molecular dynamics simulation with two different methods and binding energy calculations by MM-GBSA and MM-PBSA were adopted to determine the stability of intermolecular interactions between protein and ligands. The results showed that both these derivatives made direct contacts with the important conserved residues of the active site, where propionylshikonin demonstrated stronger binding and stability than acetylshikonin, according to molecular dynamics simulation and binding free energy calculations. Further, QM/MM energy calculation was employed to study the chemical reactivity of the propionylshikonin and also to describe the mechanism of non bonded interactions between the propionylshikonin and CREBBP bromodomain. Though this study demands in vitro and in vivo experiments to evaluate the efficiency of the compound, these insights would assist to design more potent CREBBP bromodomain inhibitor, guiding the site of modification of propionylshikonin moiety for designing selective inhibitors.
Identification of the SOX2 interactome by BioID reveals EP300 as a mediator of SOX2-dependent squamous differentiation and lung squamous cell carcinoma growth
2017, Molecular and Cellular Proteomics
Lung cancer is the leading cause of cancer mortality worldwide, with squamous cell carcinoma (SQCC) being the second most common form. SQCCs are thought to originate in bronchial basal cells through an injury response to smoking, which results in this stem cell population committing to hyperplastic squamous rather than mucinous and ciliated fates. Copy number gains in SOX2 in the region of 3q26–28 occur in 94% of SQCCs, and appear to act both early and late in disease progression by stabilizing the initial squamous injury response in stem cells and promoting growth of invasive carcinoma. Thus, anti-SOX2 targeting strategies could help treat early and/or advanced disease. Because SOX2 itself is not readily druggable, we sought to characterize SOX2 binding partners, with the hope of identifying new strategies to indirectly interfere with SOX2 activity. We now report the first use of proximity-dependent biotin labeling (BioID) to characterize the SOX2 interactome in vivo. We identified 82 high confidence SOX2-interacting partners. An interaction with the coactivator EP300 was subsequently validated in both basal cells and SQCCs, and we demonstrate that EP300 is necessary for SOX2 activity in basal cells, including for induction of the squamous fate. We also report that EP300 copy number gains are common in SQCCs and that growth of lung cancer cell lines with 3q gains, including SQCC cells, is dependent on EP300. Finally, we show that EP300 inhibitors can be combined with other targeted therapeutics to achieve more effective growth suppression. Our work supports the use of BioID to identify interacting protein partners of nondruggable oncoproteins such as SOX2, as an effective strategy to discover biologically relevant, druggable targets.
Expression of p300 and p300/CBP associated factor (PCAF) in actinic keratosis and squamous cell carcinoma of the skin
2016, Experimental and Molecular Pathology
Citation Excerpt :
The transcriptional co-factors and epigenetic modifiers p300 and PCAF have been reported to be involved in the regulation of cell proliferation, differentiation, reaction to cell damage, and apoptosis (Bedford et al., 2010; Grossman, 2001; Iyer et al., 2004). Nuclear expression was evaluated in several human carcinomas, and no association with age or gender was found (Chen et al., 2013; Cho et al., 2015; Debes et al., 2003; Hou et al., 2012; Huh et al., 2013; Ishihama et al., 2007; Li et al., 2011; Liao et al., 2012; Syrjänen et al., 2010; Vleugel et al., 2006; Xiao et al., 2011; Yokomizo et al., 2011). In our study, the presence of cytoplasmic expression and diffuse distribution of nuclear p300immunopositivity were associated with older age.
p300 and p300/CBP-associated factor (PCAF) are histone modifiers and transcriptional co-factors involved in a number of cell processes. We investigated their expression patterns in 79 actinic keratoses (AK), 45 cases of Bowen's disease (BD), and 168 invasive squamous cell carcinomas of the skin (SCC). Using tissue microarray and immunohistochemistry, we evaluated p300 and PCAF expression in relation to the type of the lesion and SCC prognostic parameters (grade, diameter, thickness and level of invasion). High nuclear expression of p300 (> 60% of positive cells) (p = 0.001) and absent cytoplasmic expression (p = 0.026) were more frequent in SCC compared to AK and BD, respectively. Cytoplasmic expression of p300 was associated with the SCC invasion of subcutaneous fat and deeper tissues (p = 0.049). Diffuse distribution of cells with p300 nuclear expression was more commonly seen in BD and SCC compared to AK (p < 0.001), in moderately- and poorly-differentiated SCC compared to well-differentiated SCC (p < 0.001), in tumors thicker than 6 mm (p < 0.001), and in deeply invading tumors (p = 0.001). More frequent loss of PCAF nuclear expression was observed in SCC than in AK and BD (p < 0.001). Diffuse distribution of cells with PCAF cytoplasmic expression was more common in BD and SCC compared to AK (p < 0.001), and in poorly-differentiated SCC compared to well- and moderately-differentiated SCC (p < 0.001). Our results suggest that increase in nuclear expression of p300, as well as the presence of cytoplasmic but loss of nuclear expression of PCAF, could play an important role in the development and progression of cutaneous SCC.

View all citing articles on Scopus

^⁎: These authors contributed equally to this work and share first authorship.

View full text

Original articleGeneral thoracicHigh Expression of p300 Has an Unfavorable Impact on Survival in Resectable Esophageal Squamous Cell Carcinoma

Background

Methods

Results

Conclusions

Section snippets

Patient Selection

Patient Characteristics

p300 Immunoreactivity Score Cutoff Value

Comment

Surgery

Am J Surg

Ann Thorac Surg

Cell

Exp Mol Pathol

FEBS Lett

Cancer Cell

Cancer statistics, 2010

CA Cancer J Clin

Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781

J Clin Oncol

Esophageal cancer

N Engl J Med