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E-MTAB-8198

ABSTRACT: Functional effect of DOT1L pharmacological inhibition in ER-positive Ovarian Cancer cells

PROVIDER: E-MTAB-8198 | ExpressionAtlas | 2025-01-16

REPOSITORIES: ExpressionAtlas

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			Action	DRS
	E-MTAB-8198-analysis-methods.tsv	Tabular
	E-MTAB-8198-analytics.tsv	Tabular
	E-MTAB-8198-atlasExperimentSummary.Rdata	Rdata
	E-MTAB-8198-configuration.xml	Xml
	E-MTAB-8198-g2_g1-mvaPlot.png	Other

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Functional effect of DOT1L pharmacological inhibition in ERα-positive Ovarian Cancer cells

Project description:Functional effect of DOT1L pharmacological inhibition in ERα-positive Ovarian Cancer cells

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Functional effect of DOT1L pharmacological inhibition in ERα-positive Ovarian Cancer cells

Project description:Estrogen Receptor alpha (ERα), a nuclear receptor with transcriptional activity, is a master regulator of estrogen signaling, widely known as therapeutic target in hormone-responsive breast cancer (BC). Moreover, ERα is highly expressed in approximately 80% of High Grade Serous Ovarian Cancer (HGSOC), the most common epithelial ovarian carcinoma. Despite some promising clinical trials evaluating endocrine therapy in this type of tumor, the role of ERα is still unknown. Epigenetic changes, such as DNA methylation, are emerging as key contributing factors to carcinogenesis. Disruptor of telomeric silencing-1-like (DOT1L), the only known histone methyl transferase capable to produce H3K79 mono, di and tri-methylation, modulates ERα actions in hormone-responsive BC. Considering this evidence, ERα-DOT1L association was confirmed in ERα-positive OC cells, PEO1 and PEO4, by Co-IP. DOT1L pharmacological inhibition by EPZ004777 (EPZ) revealed the involvement of this epigenetic enzyme in cell proliferation, cell cycle progression and apoptosis. Transcriptome profiling after ICI (a Selective Estrogen Receptor Degrader) and EPZ treatment, in both cell lines, has underlined a deep impact of both compounds on ERα-modulated genes, including the down-regulation of ERα itself. On the other hand, functional analysis showed that commonly affected transcripts are involved in different cellular processes, such as cancer cell survival, chemoresistance and cell cycle progression. Moreover, ChIP-qPCR performed on ERα promoter highlighted ERα and DOT1L co-localization, both in PEO1 and in PEO4 cells, which was reduced after EPZ treatment, suggesting a role of this complex on receptor transcriptional activity. In addition, drug combination studies performed with EPZ and ICI showed an additive effect in cell growth inhibition. Taken together, these results suggest DOT1L as a potential therapeutic target in the treatment of OC.

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The role of DOT1L in ovarian cancer growth and progression

Project description:Disruptor of telomeric silencing 1-like (DOT1L) expression is elevated in many cancer types including ovarian cancer. Therefore, we analyzed the role of DOT1L in ovarian cancer. Pharmacological inhibition of DOT1L expression in ovarian cancer cell lines resulted in decreased proliferation, and increased cell death.

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Project description:Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers but many cancers develop resistance to anti-estrogens. Cyclin-dependent kinase 8 (CDK8) is a transcriptional regulator of several oncogenic pathways. Expression levels of CDK8 and ERα are inversely correlated in breast cancers suggesting a functional association between CDK8 and ER. CDK8 inhibition by selective small-molecule inhibitors, by shRNA knockdown or by CRISPR-Cas9 knockout suppressed estrogen-induced transcription, with no significant effects on ERα protein expression or phosphorylation. CDK8 inhibition also abrogated the mitogenic effect of estrogen on ER-positive breast cancer cells and potentiated growth inhibition by the ER antagonist fulvestrant. In vivo, administration of a CDK8 inhibitor suppressed ER-positive breast cancer xenograft growth and augmented the effects of fulvestrant with no apparent toxicity. CDK8 inhibitors also suppressed the development of estrogen independence in ER-positive breast cancer cells. These results identify CDK8 as a novel drug target for breast cancer therapy.

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