Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival

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• dc.contributor.author Palma, Fatima Domenica Elisa de
• dc.contributor.author Guigó Serra, Roderic
• dc.contributor.author Salvatore, Francesco
• dc.date.accessioned 2025-03-18T07:45:54Z
• dc.date.available 2025-03-18T07:45:54Z
• dc.date.issued 2025
• dc.description Data de publicació electrònica: 20-01-2025
• dc.description.abstract Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.
• dc.format.mimetype application/pdf
• dc.identifier.citation De Palma FDE, Pol JG, Carbonnier V, Scuderi SA, Mannino D, Montégut L, et al. Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival. Cell Death Differ. 2025 Jan 20. DOI: 10.1038/s41418-024-01430-2
• dc.identifier.doi http://dx.doi.org/10.1038/s41418-024-01430-2
• dc.identifier.issn 1350-9047
• dc.identifier.uri http://hdl.handle.net/10230/69960
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Cell Death Differ. 2025 Jan 20
• dc.rights © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Diagnostic markers
• dc.subject.keyword Tumour biomarkers
• dc.title Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion