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The protein deacetylase HDAC10 controls DNA replication in malignant lymphoid cells

ABSTRACT: Histone deacetylases (HDACs) are a family of 18 epigenetic modifiers. Targets and cancer-relevant functions of HDAC10 in leukemia cells are enigmatic. We used flow cytometry, confocal immunofluorescence, single-cell DNA electrophoresis, global RNA-sequencing, mass spectrometry-based proteomics, and quantitative measurement of protein acetylation sites to evaluate how HDAC10 controls cancer-relevant signaling pathways in leukemia cells. We demonstrate that a subset of human cultured and primary acute B-cell/T-cell leukemia and lymphoma cells require HDAC10 for their survival. In such cells, HDAC10 controls a MYC-dependent transcriptional induction of the DNA polymerase subunit POLD1. Consequently, inhibition of HDAC10 halts cells in the S and G2/M phases of the cell cycle and causes DNA breaks, and an accumulation of poly-ADP-ribose chains indicating unresolved DNA damage. These processes culminate in caspase-dependent apoptosis. We reveal that HDAC10 has a nuclear function controlling the MYC-POLD1 axis. HDAC10 maintains the processivity of DNA replication and genome integrity in leukemic cell subtypes. This mechanistically defined HDAC10ness could prospectively be exploited as treatment option.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277944 | GEO | 2025/05/23

REPOSITORIES: GEO

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Project description:Cutaneous T-cell lymphomas (CTCL) are a group of rare hematological malignancies characterized by infiltration of malignant T-cells into the skin. Two main types of CTCL constitute of Mycosis Fungoides (MF), a more indolent form of the disease, and Sézary Syndrome (SS), the aggressive and leukemic variant with blood involvement. Sézary syndrome presents a significant clinical challenge due to its very aggressive nature, poor prognosis, and treatment resistance, and to date, the disease is known to be uncurable. Histone deacetylase inhibitors have gained attention in CTCL treatment with promising results, but they expose limited specificity and strong side effects. Recent genomic studies underscore the role of epigenetic modifiers in CTCL pathogenesis, prompting an investigation into HDAC10, a member of Class IIb HDACs, in SS. HDAC10 was investigated in different cancers, revealing its involvement in the cell cycle regulation, apoptosis, and autophagy, but its role in CTCL is unknown. In this study we aimed to determine the role of HDAC10 in Sezary Syndrome, focusing on its cellular localization, role in cell growth, and potential therapeutic target. We indicated that HDAC10 is overexpressed in SS patients and located mainly in the cytoplasm. Its overexpression leads to an inhibitory effect on apoptosis progression when exposed to the pro-apoptotic compound Camptothecin (CPT). Knockdown of HDAC10 resulted in reduced cell growth and induction of apoptosis and autophagy, highlighting its potential importance in CTCL pathogenesis. Whole transcriptome analysis indicated that HDAC10 is associated with crucial cancer-related pathways for example hematopoietic cell lineage, PI3K-Akt signaling pathway, pathways in cancer, Ras signaling pathway, MAPK signaling pathway or JAK-STAT signaling pathway, which are critical for the survival and proliferation of malignant T cells. Inhibition of HDAC10 with selective HDAC10i increased the sensitivity of Sézary cells to the pro-apoptotic compound camptothecin (CPT). Our findings demonstrate that HDAC10 plays a key role in the molecular background of Sézary syndrome, highlighting its importance in the cellular mechanisms of the disease

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The protein deacetylase HDAC10 controls DNA replication in malignant lymphoid cells

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