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The Epigenetic Modifiers HDAC2 and HDAC7 Inversely Associate with Cancer Stemness and Immunity in Solid Tumors. Int. J. Mol. Sci. 2024, 25, 7841. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms25147841  \nAcademic Editor: Sonia Emanuele  \nReceived: 28 May 2024  \nRevised: 7 July 2024  \nAccepted: 13 July 2024  \nPublished: 17 July 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Undergraduate Research Group “Biobase”, Poznan University of Medical Sciences, 61-701 Poznan, Poland; [maciejewskikacper@mensa.org.pl](maciejewskikacper@mensa.org.pl) (K.M.); [marek.giers00@gmail.com](marek.giers00@gmail.com) (M.G.)  \n2 Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland  \n3 Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland  \n* [Correspondence: u.oleksiewicz@gmail.com](Correspondence: u.oleksiewicz@gmail.com) (U.O.); [czerwinska.patrycja@ump.edu.pl](czerwinska.patrycja@ump.edu.pl) (P.C.)  \nAbstract: Dysregulation of histone deacetylases (HDACs) is closely associated with cancer development and progression. Here, we comprehensively analyzed the association between all HDAC family members and several clinicopathological and molecular traits of solid tumors across 22 distinct tumor types, focusing primarily on cancer stemness and immunity. To this end, we used publicly available TCGA data and several bioinformatic tools (i.e., GEPIA2, TISIDB, GSCA, Enrichr, GSEA). Our analyses revealed that class I and class II HDAC proteins are associated with distinct cancer phenotypes. The transcriptomic profiling indicated that class I HDAC members, including HDAC2, are positively associated with cancer stemness, while class IIA HDAC proteins, represented by HDAC7, show a negative correlation to cancer stem cell-like phenotypes in solid tumors. In contrast to tumors with high amounts of HDAC7 proteins, the transcriptome signatures of HDAC2-overexpressing cancers are significantly enriched with biological terms previously determined as stemness-associated genes. Moreover, high HDAC2-expressing tumors are depleted with immune-related processes, and HDAC2 expression correlates with tumor immunosuppressive microenvironments. On the contrary, HDAC7 upregulation is significantly associated with enhanced immune responses, followed by enriched infiltration of CD4+ and CD8+ T cells. This is the first comprehensive report demonstrating robust and versatile associations between specific HDAC family members, cancer dedifferentiation, and anti-tumor immune statuses in solid tumors.  \nKeywords: HDAC; cancer stemness; immunotherapy; tumor immunity; transcriptomics; TCGA  \n1. Introduction  \nSolid tumors are biologically complex structures with substantial intratumor heterogeneity that contain transformed cancer cells, supportive cells, and tumor-infiltrating cells [1] . Also, tumor cells significantly differ in the potency to initiate and maintain tumor growth, with stem-like cancer cells exhibiting the highest self-renewal potency, responding rapidly and flexibly to environmental challenges and becoming a primary source of drug-resistant tumor cells [2] . Stem cell-associated molecular features of cancer cells might be acquired by the bulk tumor cells, i.e., in response to exogenous stimuli. Later on, those cells may experience phases of t","cbCailDTmuJ5va2F","https://ap.wps.com/l/cbCailDTmuJ5va2F","pdf",9538020,25,"English","# Introduction\n## Cancer stemness and tumor heterogeneity\n## Cancer stemness and antitumor immunity\n## Epigenetic mechanisms in cancer progression","[{\"question\":\"Which HDAC proteins were examined and how did they relate to cancer stemness?\",\"answer\":\"The study focused on HDAC2 and HDAC7 within the HDAC family. HDAC2 showed a positive association with cancer stemness, whereas HDAC7 was negatively associated with cancer stem cell-like phenotypes in solid tumors.\"},{\"question\":\"What relationship did the findings show between HDAC2 expression and tumor immunity?\",\"answer\":\"High HDAC2-expressing tumors were depleted in immune-related processes, and HDAC2 correlated with tumor immunosuppressive microenvironments.\"},{\"question\":\"How did HDAC7 upregulation affect immune responses and T-cell infiltration?\",\"answer\":\"HDAC7 upregulation was associated with enhanced immune responses and enriched infiltration of CD4+ and CD8+ T cells.\"}]","The Epigenetic Modifiers HDAC2 and HDAC7 Inversely Associate with Cancer Stemness and Immunity in Solid Tumors | PDF",1790021465,63]