Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia

Feng, Zizhen; Yao, Yuan; Zhou, Chao; Chen, Ken; Wu, Feng; Wei, Liping; Liu, Wei; Dong, Shuang; Redell, Michele S.; Mo, Qianxing; Song, Yuanlin

doi:10.1186/s13045-016-0252-7

Cited by 94 publications

(79 citation statements)

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“…These findings need to be considered because Lsd1 inhibitors entered clinical trials, for example in the treatment of mixed-lineage leukemia (Feng et al., 2016). In conclusion, our data identify Lsd1 as a key epigenetic regulator of BAT metabolism.…”

Section: Discussionmentioning

confidence: 99%

Lsd1 Ablation Triggers Metabolic Reprogramming of Brown Adipose Tissue

Duteil¹,

Tošić²,

Lausecker³

et al. 2016

Cell Reports

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SummaryPrevious work indicated that lysine-specific demethylase 1 (Lsd1) can positively regulate the oxidative and thermogenic capacities of white and beige adipocytes. Here we investigate the role of Lsd1 in brown adipose tissue (BAT) and find that BAT-selective Lsd1 ablation induces a shift from oxidative to glycolytic metabolism. This shift is associated with downregulation of BAT-specific and upregulation of white adipose tissue (WAT)-selective gene expression. This results in the accumulation of di- and triacylglycerides and culminates in a profound whitening of BAT in aged Lsd1-deficient mice. Further studies show that Lsd1 maintains BAT properties via a dual role. It activates BAT-selective gene expression in concert with the transcription factor Nrf1 and represses WAT-selective genes through recruitment of the CoREST complex. In conclusion, our data uncover Lsd1 as a key regulator of gene expression and metabolic function in BAT.

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Section: Discussionmentioning

confidence: 99%

Lsd1 Ablation Triggers Metabolic Reprogramming of Brown Adipose Tissue

Duteil¹,

Tošić²,

Lausecker³

et al. 2016

Cell Reports

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“…Cell cycle and cell apoptosis analyses were determined by flow cytometry (BD, UA) [27, 28]. In this experiment, the SK-OV-3 and TOV21G cells were treated with 10 μM SGC0946 and EPZ004777 for 12 days, respectively.…”

Section: Methodsmentioning

confidence: 99%

Prognostic and therapeutic value of disruptor of telomeric silencing-1-like (DOT1L) expression in patients with ovarian cancer

Zhang

Liu

et al. 2017

J Hematol Oncol

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BackgroundEpigenetics has been known to play a critical role in regulating the malignant phenotype. This study was designed to examine the expression of DOT1L (histone 3 lysine 79 methyltransferase) and H3K79 methylation in normal ovarian tissues and ovarian tumors and to explore the function of DOT1L and its underline mechanisms in ovarian cancer.MethodsThe expression of DOT1L and H3K79 methylation in 250 ovarian tumor samples and 24 normal ovarian samples was assessed by immunohistochemistry. The effects of DOT1L on cell proliferation in vitro were evaluated using CCK8, colony formation and flow cytometry. The DOT1L-targeted genes were determined using chromatin immune-precipitation coupled with high-throughput sequencing (ChIP-seq) and ChIP-PCR. Gene expression levels were measured by real-time PCR and immunoblotting. The effects of DOT1L on tumor growth in vivo were evaluated using an orthotopic ovarian tumor model.ResultsDOT1L expression and H3K79 methylation was significantly increased in malignant ovarian tumors. High DOT1L expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, histologic grade, and lymphatic metastasis. DOT1L was an independent prognostic factor for the overall survival (OS) and progression-free survival (PFS) of ovarian cancer, and higher DOT1L expression was associated with poorer OS and PFS. Furthermore, DOT1L regulates the transcription of G1 phase genes CDK6 and CCND3 through H3K79 dimethylation; therefore, blocking DOT1L could result in G1 arrest and thereby impede the cell proliferation in vitro and tumor growth in vivo.ConclusionsOur findings first demonstrate that DOT1L over-expression has important clinical significance in ovarian cancer and also clarify that it drives cell cycle progression through transcriptional regulation of CDK6 and CCND3 through H3K79 methylation, suggesting that DOT1L might be potential target for prognostic assessment and therapeutic intervention in ovarian cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0400-8) contains supplementary material, which is available to authorized users.

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“…Therefore, other efforts to target this epigenetic disease are focused on the function of WT MLL. There has been some investigation into using LSD1 inhibitors to restore the balance between MLL and LSD1 in H3K4 methylation (172). Other groups are using compounds that specifically inhibit the SET-WDR5 interaction in order to inhibit the WT MLL complex (42, 173).…”

Section: Bivalent Epigenetic Therapymentioning

confidence: 99%

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

Zaidi

Frietze

Gordon

et al. 2017

Molecular and Cellular Biology

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Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G 1 phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency, suggesting a mechanism by which cancer cells reacquire properties that are characteristic of undifferentiated, multipotent cells. This bivalent epigenetic control of oncofetal gene expression in cancer cells may offer novel insights into the onset and progression of cancer and may provide specific and selective options for diagnosis as well as for therapeutic intervention.KEYWORDS bivalency, cancer, epigenetic control, nuclear structure, oncofetal gene expression E pigenetic control of gene expression plays a pivotal role in physiological responsiveness and is often compromised during onset and progression of cancer. Epigenetic changes are heritable but do not involve changes in DNA sequences. Within a given cell, there are many distinct carriers of epigenetic information that are relayed to progeny upon cell division. Epigenetic mechanisms include methylation of CpG residues, modifications of nucleosomal histone proteins, regulation of gene transcription and protein translation by noncoding RNA molecules, and mitotic retention of transcription factors (1)(2)(3)(4)(5)(6)(7)(8). From an architectural perspective, epigenetic control is engaged at multiple levels of nuclear organization from sequence-specific regulatory elements to chromatin remodeling at the nucleosomal level to large-scale inter-and intrachromosomal interactions (9)(10)(11)(12)(13)(14). These epigenetic mechanisms function in a complex but coordinated manner to orchestrate cellular responses to extracellular signals.The cellular epigenetic landscape is dynamically modified by a number of posttranslational modifications of nucleosomal histones (1,3,15,16). These modifications function in concert-a phenomenon described as the histone code-to establish context-dependent chromatin landscapes that control access of transcription factors to gene regulatory regions (1,3,15,16). This review focuses on the bivalent chromatin landscape defined by addition of three methyl moieties to lysine 4 and lysine 27 residues of histone H3 (referred to as histone 3 lysine 4 me3 [H3K4me3] and H3K27me3 throughout this article). Chromatin bivalency, i.e., the presence of both activating H3K4me3 and repressive H3K27me3 modifications at gene promoters, was first ob- Address correspondence to Gary S. Stein, gary.stein@med.uvm.edu. MINIREVIEW cr...

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Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia

Cited by 94 publications

References 50 publications

Lsd1 Ablation Triggers Metabolic Reprogramming of Brown Adipose Tissue

Lsd1 Ablation Triggers Metabolic Reprogramming of Brown Adipose Tissue

Prognostic and therapeutic value of disruptor of telomeric silencing-1-like (DOT1L) expression in patients with ovarian cancer

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

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