2. Academic Validation
  3. HDAC Inhibition Induces Transient Phenotypic Inertia in Dormant OCCC Spheroids by Derepression of Cell Cycle Genes

HDAC Inhibition Induces Transient Phenotypic Inertia in Dormant OCCC Spheroids by Derepression of Cell Cycle Genes

  • Cells. 2026 Apr 10;15(8):673. doi: 10.3390/cells15080673.
Sylvia Cheng 1 2,  Bart Kolendowski 1 3,  Yudith Ramos-Valdes 1 3,  Trevor G Shepherd 1 3 4 5 6,  Gabriel E DiMattia 1 2 3 4
Affiliations

Affiliations

  • 1 Mary & John Knight Translational Ovarian Cancer Research Unit, Verspeeten Family Cancer Centre, London, ON N6A 4L6, Canada.
  • 2 Department of Biochemistry, Western University, London, ON N6A 3K7, Canada.
  • 3 London Health Sciences Centre Research Institute, London, ON N6A 4L6, Canada.
  • 4 Department of Oncology, Western University, London, ON N6A 3K7, Canada.
  • 5 Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada.
  • 6 Department of Obstetrics & Gynaecology, Western University, London, ON N6A 3K7, Canada.
PMID: 42041541 DOI: 10.3390/cells15080673
Abstract

Multicellular Cancer cell aggregates, termed spheroids, are anoikis-resistant, avascular, heterogeneous structures responsible for transcoelomic metastasis of ovarian clear cell carcinoma (OCCC). OCCC is a rare subtype of ovarian Cancer with high ARID1A gene mutation rates, resulting in genome-wide changes to H3K27Ac levels and histone deacetylase (HDAC) function. Our study investigated the utility of HDAC Inhibitor (HDACi) treatment and H3K27Ac dynamics in OCCC spheroids. By comparing KOC-7c and 105C OCCC cell lines, which have opposing abilities to proliferate as spheroids, we revealed that KOC-7c and 105C spheroids differentially regulated H3K27Ac levels, which correlated with the sensitivity of KOC-7c and the resistance of 105C spheroids to H3K27Ac-altering HDACi treatment. RNA-seq of Entinostat-treated versus vehicle-treated spheroids resulted in a dramatic change in the 105C spheroid transcriptome such that it more closely resembled the proliferative KOC-7c transcriptome over the short term. Comparative pathway analysis identified preferential de-repression of a G2/M checkpoint gene program in 105C spheroids upon Entinostat treatment when compared directly to the KOC-7c spheroids. Our results suggest that the utility of HDACi in OCCC is highly context-dependent.

Keywords

ACY1215; Entinostat; HDAC inhibitor; cancer; cell line; clear cell; dormancy; ovarian; spheroid.

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