ArticleCancer cell international2022
Combinatorial targeting of menin and the histone methyltransferase DOT1L as a novel therapeutic strategy for treatment of chemotherapy-resistant ovarian cancer.
Article in Cancer cell international, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 20 citations in OpenAlex.
- Hsa-miR-149-5p targets Men1 to inhibit the progression of gastric cancer through the HSPA6/JNK pathway.Cancer cell international · 2026Article
- Case Report: Investigation and characterization of a multiple endocrine neoplasia type 1 case and its pedigree.Frontiers in endocrinology · 2026Article
- BRPF1 in cancer epigenetics: a key regulator of histone acetylation and a promising therapeutic target.Cell death discovery · 2025Review
- Menin regulates YBX1 nucleus translocation to boost the HKDC1 transcription and affects pancreatic cancer glycolysis.iScience · 2025Article
- Menin: from molecular insights to clinical impact.Epigenomics · 2025Review
- BRPF1 inhibition reduces migration and invasion of metastatic ovarian cancer cells, representing a potential therapeutic target.Scientific reports · 2025Article
- Menin inhibitor MI-503 exhibits potent anti-cancer activity in osteosarcoma.Scientific reports · 2025Article
- Menin in Cancer.Genes · 2024Review
- Transcriptome Study in Sicilian Patients with Autism Spectrum Disorder.Biomedicines · 2024Article
- PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer.Molecular cancer · 2024Article
- Genome-wide DNA methylation changes upon DOT1L inhibition in hormone-responsive breast cancer cells.Frontiers in cell and developmental biology · 2023Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundOvarian cancer (OC) is characterized by a low response rate and high frequency of resistance development to currently available treatments. The therapeutic potential of histone methyltransferase DOT1L inhibitor in OC cells has been demonstrated, but optimal efficacy and safety of this targeted therapy approach still require improvement. We set forth to evaluate if this problem can be overcome by combinatorial targeting of this epigenetic modifier and menin, one of its functional partners in chromatin.
methodssiRNA-mediated gene knock-down and pharmacological inhibition of menin, a key component of the MLL/SET1 complex and a fitness gene in OC cells, coupled to cell proliferation assays on a panel of high grade serous OC cell lines, including chemotherapy-sensitive and -resistant clones, were applied in order to evaluate how depletion or blockade of this enzyme influences growth and viability of OC cells. RNA sequencing was applied to identify menin target genes and pathways, and the effects of combined inhibition of menin and DOT1L on growth and transcriptome of these OC models were evaluated.
resultsSilencing and pharmacological inhibition of menin exert antiproliferative effects in all OC cells tested and, in PEO1 and PEO4 cells, a profound impact on transcriptome via down-regulation of cell cycle regulatory pathways, aryl hydrocarbon receptor, MYC and KRAS signalling. We demonstrated association of menin and DOT1L in OC cells and identified a subset of genes co-regulated by the two factors. Interestingly, co-treatment with DOT1L and menin pharmacological inhibitors exerts an additive effect on growth inhibition on chemotherapy-sensitive and -refractory OC cells mediated by transcriptome changes controlled by menin and DOT1L activities.
conclusionThese results indicate that menin functionally cooperates with DOT1L in OC cells modulating transcription of genes involved in key cellular functions including, among others, cell proliferation and survival, that are strongly affected by combined inhibition of these two epigenetic regulators, suggesting that this may represent a novel therapeutic strategy for chemotherapy-resistant OCs.
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