Genetic dysregulation of EP300 in cancers in light of cancer epigenome control - targeting of p300-proficient and-deficient cancers

Sep 21, 2026

Uploaded by Riley

Cancer is driven by multistep accumulation of genetic alterations alongside non-genetic epigenetic mechanisms that reshape gene expression without changing DNA sequence. Frequent EP300 mutations in bladder, cervical, and uterine cancers disrupt p300 histone acetyltransferase function, influencing initiation and progression. Review findings link EP300 copy-number changes, truncating mutations, and abnormal transcription with tumor grade, metastasis, and survival. EP300 expression also associates with mRNA elevation of cooperative epigenetic and chromatin-remodeling factors, informing prognosis and therapeutic targeting.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

Introduction

Epigenetic mechanisms in cancer development

Histone acetylation and HAT/HDAC balance

EP300 dysregulation and cancer progression

Therapeutic strategies targeting EP300

Genetic dysregulation of EP300 in cancers in light of cancer epigenome control – targeting of p300-proﬁcient and-deﬁcient cancers Karolina Gronkowska 1,2 and Agnieszka Robaszkiewicz 1 1Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; 2Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland Some cancer types including bladder, cervical, and uterine cancers are characterized by frequent mutations in EP300 that encode histone acetyltransferase p300. This enzyme can act both as a tumor suppressor and oncogene. In this review, we describe the role of p300 in cancer initiation and progression regarding EP300 aberrations that have been identiﬁed in TGCA Pan-Cancer Atlas studies and we also discuss possible anticancer strategies that target EP300 mutated cancers. Copy number alterations, truncating mutations, and abnormal EP300 transcriptions that affect p300 abundance and activity are associated with several pathological features such as tumor grading, metastases, and patient survival. Elevated EP300 correlates with a higher mRNA level of other epigenetic factors and chromatin remodeling enzymes that co-operate with p300 in creating permissive conditions for malignant transformation, tumor growth and metastases. The status of EP300 expression can be considered as a prognostic marker for anticancer immunotherapy efﬁcacy, as EP300 mutations are followed by an increased expression of PDL-1.HAT activators such as CTB or YF2 can be applied for p300-deﬁcient patients, whereas the natural and synthetic inhibitors of p300 activity, as well as dual HAT/bromodomain inhibitors and the PROTAC degradation of p300, may serve as strategies in the ﬁght against p300-fueled cancers. INTRODUCTION Cancer is considered a complex disease, being a multistep process associated with the accumulation of genetic alterations. However, it is now widely accepted that non-genetic factors also contribute to cancer development and progression, 1 represented by inter alia epigenetic mechanisms that alter gene expression patterns without changing the DNA sequence. Epigenetic changes can be divided into three main categories: the modiﬁcation of nucleic acids (such as DNA methylation), post-translational modiﬁcations (PTMs) of histone tails, and the alteration of gene expression by non-coding RNAs (e.g., microRNAs [miRNAs] and long non-coding RNAs [lncRNAs]) .2 The ﬁrst two groups represent the covalent modiﬁcations of nucleotides and amino acid residues, usually working together to integrate regulatory inputs and leading to coordinated alteration in chromatin structure and function. This deﬁnes the cell transcriptomes at the earliest step of RNA synthesis. The existence of many combinations of modiﬁcations that are either more likely to occur together, or mutually exclusive, suggest a functional crosstalk between some epigenetic marks. This can occur between modiﬁed DNA and histones, distinct modiﬁcations on the same histone tail, on neighboring histones within the same nucleosome, or on neighboring nucleosomes in a chromatin domain. Well-described modiﬁcations include acetylation, methylation, phosphorylation, ADP ribosylation, ubiquitination, citrullination, and SUMOylation,3 which regulate the nucleosome structure and dynamics by directly altering histone-histone or DNA-histone interactions and by recruiting chromatin remodeling enzymes resulting in positive and negative feedback loops.4,5 Various histone modiﬁcations that are altered by aberrantly expressed modiﬁer enzymes contribute to tumor development, progression, and metastasis. Among them, altered histone acetylationis most frequently referred to.6 This modiﬁcation usually marks active transcription, as it neutralizes the positive charge on the histone lysine residues, thereby facilitating nucleos

FAQs

What role does EP300/p300 play in cancer according to the review?

EP300 encodes the histone acetyltransferase p300, which can function as both a tumor suppressor and an oncogene depending on context. EP300 aberrations are discussed as relevant to cancer initiation and progression.

Which genetic and molecular alterations of EP300 are linked to cancer outcomes?

The review associates EP300 copy number alterations, truncating mutations, and abnormal EP300 transcription with pathological features such as tumor grading, metastases, and patient survival.

How can EP300 status be used in therapy and prognosis?

EP300 expression is proposed as a prognostic marker for anticancer immunotherapy efficacy, with EP300 mutations linked to increased PDL-1 expression. The review also discusses HAT activators for p300-deficient cancers and multiple inhibitor/degradation strategies for p300-driven cancers.

Sep 21, 2026

Uploaded by Riley