The Histone Methyltransferase DOT1L Is a Functional Component of Estrogen Receptor Alpha Signaling in Ovarian Cancer Cells

Abstract

Although a large fraction of high-grade serous epithelial ovarian cancers (OCs) expresses Estrogen Receptor alpha (ERα), anti-estrogen-based therapies are still not widely used against these tumors due to a lack of sufficient evidence. The histone methyltransferase Disruptor of telomeric silencing-1-like (DOT1L), which is a modulator of ERα transcriptional activity in breast cancer, controls chromatin functions involved in tumor initiation and progression and has been proposed as a prognostic OC biomarker. As molecular and clinico-pathological data from TCGA suggest a correlation between ERα and DOT1L expression and OC prognosis, the presence and significance of ERα/DOT1L association was investigated in chemotherapy-sensitive and chemotherapy-resistant ER+ OC cells. RNA sequencing before and after inhibition of these factors showed that their activity is implicated in OC cell proliferation and that they functionally cooperate with each other to control the transcription of genes involved in key cancer cell features, such as the cell cycle, epithelial-mesenchymal transition (EMT), drug metabolism, and cell-to-cell signaling, as well as expression of the ERα gene itself. Together with evidence from loss-of-function genetic screens showing that ERα and DOT1L behave as core fitness factors in OC cells, these results suggest that combined inhibition of their activity might be effective against ERα-expressing, chemotherapy-resistant ovarian tumors.

An Overview of Candidate Therapeutic Target Genes in Ovarian Cancer

“…Epigenetic mechanisms have emerged as contributing factors to carcinogenesis. A recent work from our group elucidated the role of the DOT1L (disruptor of telomeric silencing-1-like) gene as a regulator of ERα activity in estrogen-responsive OCs [ 80 ]. DOT1L, a histone methyl transferase, acts as transcriptional regulator through H3K79 mono-, di-, and tri-methylation.…”

Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer

“…Recently, we demonstrated the key role of the previously identified DOT1L (disruptor of telomeric silencing-1-like) ERα partner [86] in hormone-responsive and endocrine-resistant BC cells [87]. DOT1L catalyzes the mono-, di-and trimethylation of Histone H3 on Lysine-79 (K79); it is involved in different biological processes, such as DNA repair, transcriptional elongation and cell cycle progression and its enrollment in cancer progression has been widely demonstrated in different types of cancers, such as in mixed-lineage leukemia (MLL) in which participates in producing MLL fusion proteins, sustaining leukemogenesis processes [104], prostate cancer [105] and ovarian cancer [106]. Our investigation revealed that its silencing or pharmacological inhibition causes a reduced hormone-responsive BC cell proliferation rate and increased cell death both in vitro and in vivo.…”

Estrogen Receptor Signaling in Cancer

“…The two original articles both describe studies with ER-coregulators, which control the transcriptional activity of ER [ 1 , 2 ]. A study by Dominic Jones et al [ 1 ] focusses on the role of the histone demethylases KDM3A and KDM4B in breast cancer and this report describes a co-operative mechanism regulating the chromatin transactivation of the ER.…”

“…As such, their targeting could be a possible therapeutic strategy. The study by Salvati et al [ 2 ] investigated the role of the histone methyltransferase disruptor of telomeric silencing-1-like (DOT1L) in high grade serous ovarian cancer (HGSOC), the predominant form of epithelial ovarian cancer. Having demonstrated that HGSOC cancers with high co-expression of both estrogen receptor alpha (ERα) and DOT1L are associated with poor survival, the investigators used cell line models to investigate functional co-operation between ERα and DOT1L.…”

“…The inhibition of DOT1L resulted in growth inhibition and modified the transcription of genes associated with invasion/migration and cell signaling in addition to the transcription of ESR1 (the ERα gene). The inhibition of both DOT1L and ER showed additive effects on cell growth and their dual inhibition is suggested as a means to enhance the current effects of endocrine therapy [ 2 ]. Together, these two studies point to the potential value of targeting ER-coregulators.…”