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
  • 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.
Products