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

• Published in: Molecular Therapy Oncology Vol. 32; no. 4; p. 200871
• Main Authors: Gronkowska, Karolina, Robaszkiewicz, Agnieszka
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.12.2024; American Society of Gene & Cell Therapy; Elsevier
• Subjects: cancer epigenetics; cancer therapy; histone acetyltransferase; MT: Regular Issue; p300; post-translational modifications; Review; p300; cancer therapy; MT: Regular Issue; post-translational modifications; cancer epigenetics; histone acetyltransferase
• ISSN: 2950-3299; 2950-3299
• DOI: 10.1016/j.omton.2024.200871

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. [Display omitted] Robaszkiewicz and Gronkowska describe the association of EP300 up- and downregulation with considerable alteration in the expression of other epigenetic enzymes in cancers. The joint deregulation of these proteins may promote cancer progression by adapting chromatin structure to allow desired profile of gene transcription.