Inhibition of histone methyltransferase DOT1L silences ERα gene and blocks proliferation of antiestrogen-resistant breast cancer cells

Nassa, Giovanni; Salvati, Annamaria; Tarallo, Roberta; Gigantino, Valerio; Alexandrova, Elena; Memoli, Domenico; Sellitto, Assunta; Rizzo, Francesca; Malanga, Donatella; Mirante, Teresa; Morelli, Eugenio; Nees, Matthias; Åkerfelt, Malin; Kangaspeska, Sara; Nyman, Tuula A.; Milanesi, Luciano; Giurato, Giorgio; Weisz, Alessandro

doi:10.1126/sciadv.aav5590

Cited by 68 publications

(72 citation statements)

References 53 publications

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“…Histone methylase Disruptor silencing 1 like (DOT1L) has been implicated in breast cancer and lymph node metastasis [131]. It donates methyl group to histone H3K79 from SAM.…”

Section: Histone Modifications and Their Role Is Breast Cancer Metastmentioning

confidence: 99%

A three layered histone epigenetics in breast cancer metastasis

2020

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Thanks to the advancement in science and technology and a significant number of cancer research programs being carried out throughout the world, the prevention, prognosis and treatment of breast cancer are improving with a positive and steady pace. However, a stern thoughtful attention is required for the metastatic breast cancer casesthe deadliest of all types of breast cancer, with a character of relapse even when treated. In an effort to explore the less travelled avenues, we summarize here studies underlying the aspects of histone epigenetics in breast cancer metastasis. Authoritative reviews on breast cancer epigenetics are already available; however, there is an urgent need to focus on the epigenetics involved in metastatic character of this cancer. Here we put forward a comprehensive review on how different layers of histone epigenetics comprising of histone chaperones, histone variants and histone modifications interplay to create breast cancer metastasis landscape. Finally, we propose a hypothesis of integrating histone-epigenetic factors as biomarkers that encompass different breast cancer subtypes and hence could be exploited as a target of larger population.

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“…Histone methylase Disruptor silencing 1 like (DOT1L) has been implicated in breast cancer and lymph node metastasis [131]. It donates methyl group to histone H3K79 from SAM.…”

Section: Histone Modifications and Their Role Is Breast Cancer Metastmentioning

confidence: 99%

A three layered histone epigenetics in breast cancer metastasis

2020

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“…Indeed, DOT1, the yeast homolog of DOT1L, suppresses senescence (Kozak et al, 2010), and DOT1L plays a protective role in UV-induced melanomagenesis (Zhu et al, 2018). In contrast, other studies have associated decreased H3K79 methylation and DOT1L expression with loss of proliferation and senescence (Barry et al, 2009;Jones et al, 2008;Kim et al, 2012;Nassa et al, 2019;Roidl et al, 2016;Song et al, 2020;Yang et al, 2019;Zhang et al, 2014). The discrepancy between these studies is not clear.…”

Section: Discussionmentioning

confidence: 98%

DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

Leon

Buj

Lesko

et al. 2020

Preprint

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Cellular senescence is characterized as a stable cell cycle arrest that can occur as a stress response associated with oncogenic activation, termed oncogene-induced senescence (OIS). Cells undergoing OIS acquire a unique microenvironment termed the senescence-associated secretory phenotype (SASP), which can be both beneficial and detrimental in a context-dependent manner. Additionally, senescent cells are characterized by robust changes in their epigenome. Here, we globally assessed the histone landscape of cells induced to senesce by oncogenic RAS and discovered a novel epigenetic regulatory mechanism of the key SASP regulator IL1A. OIS cells displayed increased di- and tri-methylation of histone H3 lysine 79 (H3K79me2/3), two active histone marks. Depletion of the H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) during OIS resulted in decreased H3K79me2/3 occupancy at the IL1A gene locus, which corresponded to decreased IL1A mRNA and cell surface expression. Decreased expression and secretion of downstream cytokines without a change in senescence markers were also observed upon DOT1L depletion. Overexpression of DOT1L increased H3K79me2/3 occupancy at the IL1A locus and upregulated the SASP, indicating that DOT1L is both necessary and sufficient for SASP gene expression. Mechanistically, we found that STING, an essential mediator of SASP transcription, is upstream of DOT1L in the epigenetic regulation of the SASP. Together, our studies establish DOT1L as an epigenetic regulator of the SASP whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.

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“…TNBCs exhibiting aberrant DOT1L expression eventually undergo EMT. This process is strongly associated with cancer cell metastasis to other organs [46], which is a main cause of lethality in all BC cases [47]. Since cancer metastasis is a multistep process including cell migration and invasion, we determined whether F-NepA is able to regulate the metastatic potential of human TNBC cells via the inhibition of these two processes which might be coincident with DOT1L expression.…”

Section: F-nepa Modulates Emt-associated Gene Expressions In Human Tnmentioning

confidence: 99%

Antiproliferative and Antimigration Activities of Fluoro-Neplanocin A via Inhibition of Histone H3 Methylation in Triple-Negative Breast Cancer

et al. 2020

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Triple-negative breast cancer (TNBC) is among the most aggressive and potentially metastatic malignancies. Most affected patients have poor clinical outcomes due to the lack of specific molecular targets on tumor cells. The upregulated expression of disruptor of telomeric silencing 1-like (DOT1L), a histone methyltransferase specific for the histone H3 lysine 79 residue (H3K79), is strongly correlated with TNBC cell aggressiveness. Therefore, DOT1L is considered a potential molecular target in TNBC. Fluoro-neplanocin A (F-NepA), an inhibitor of S-adenosylhomocysteine hydrolase, exhibited potent antiproliferative activity against various types of cancer cells, including breast cancers. However, the molecular mechanism underlying the anticancer activity of F-NepA in TNBC cells remains to be elucidated. We determined that F-NepA exhibited a higher growth-inhibitory activity against TNBC cells relative to non-TNBC breast cancer and normal breast epithelial cells. Moreover, F-NepA effectively downregulated the level of H3K79me2 in MDA-MB-231 TNBC cells by inhibiting DOT1L activity. F-NepA also significantly inhibited TNBC cell migration and invasion. These activities of F-NepA might be associated with the upregulation of E-cadherin and downregulation of N-cadherin and Vimentin in TNBC cells. Taken together, these data highlight F-NepA as a strong potential candidate for the targeted treatment of high-DOT1L-expressing TNBC.

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Inhibition of histone methyltransferase DOT1L silences ERα gene and blocks proliferation of antiestrogen-resistant breast cancer cells

Abstract: Pharmacological inhibition of DOT1L blocks estrogen receptor signaling in breast cancer.

Cited by 68 publications

References 53 publications

A three layered histone epigenetics in breast cancer metastasis

A three layered histone epigenetics in breast cancer metastasis

DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

Antiproliferative and Antimigration Activities of Fluoro-Neplanocin A via Inhibition of Histone H3 Methylation in Triple-Negative Breast Cancer

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