Abstract

   E1A Binding Protein P300 (EP300) is one of the mutations of genes
   involved in histone modifications in esophageal squamous cell carcinoma
   (ESCC). However, its clinical relevance, potential function and
   mechanisms have remained elusive.

   Methods: Genomic sequencing datas from 325 esophageal squamous cell
   carcinoma (ESCC) cases were integrated and screened a series of
   frequently mutated histone modifier genes. EP300 was selected to
   further analyze its clinical significance, function and RNA-sequencing
   was performed to explore its potential mechanism.

   Results: Of 35 histone modifier genes, EP300 was not only a
   significantly mutated gene but also a frequently mutated gene with a
   mutation frequency of more than 10% in ESCC. EP300 mutation was
   associated with tumor grade, pathological T stage and lymph node
   metastasis, predicting a shorter cumulative survival status.
   Immunohistochemical analysis showed that EP300 expression was
   significantly higher in ESCC tumor tissues, and the expression levels
   were associated with poor survival of ESCC patients. Moreover, we found
   that EP300 knockdown led to inhibition of cell proliferation, colony
   formation, migration and invasion. RNA-sequencing showed EP300
   knockdown led to a significant change of genes expression associated
   with angiogenesis, hypoxia and epithelial-to-mesenchymal transition
   (EMT).

   Conclusions: Taken together, our study identified a novel role and
   mechanism of EP300 in ESCC and provided epigenetic therapeutic
   strategies for the treatment of ESCC.

   Keywords: EP300, ESCC, prognosis, angiogenesis, EMT

Introduction

   Esophageal cancer is the sixth most lethal cancer worldwide with more
   than 400,000 deaths each year and approximately 70% of global cases
   occurring in China, where the dominant histologic type is esophageal
   squamous cell carcinoma (ESCC) [81]^1. Unlike other gastrointestinal
   tumors such as gastric cancer and colon cancer that have been
   extensively studied, the achievements of ESCC remains unchanged in the
   past few decades, with limited clinical approaches for early diagnosis
   and a five-year survival rate ranging from 15% to 25%[82]^2. However,
   most recently, a succession of great achievements has been made in ESCC
   cancer genomics with the advent and progression of high-throughput
   next-generation sequencing (NGS) [83]^3^-[84]^7. The new generation of
   sequencing technology not only can be no preferences to reflect genomic