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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.