Deficiency of H3K79 Histone Methyltransferase Dot1-like Protein (DOT1L) Inhibits Cell Proliferation

Kim, Wootae; Kim, Ranah; Park, Geunyeong; Park, Jong-Wan; Kim, Ja Eun

doi:10.1074/jbc.m111.328138

Cited by 117 publications

(119 citation statements)

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“…Treatment of MLL-rearranged leukemia with EPZ00477 or EPZ-5676 (potent and selective aminonucleoside inhibitors of DOT1L histone methyltransferase activity) causes cell death in acute leukemia lines bearing MLL translocations (33,34). Down-regulation of H3K79 methyltransferase, DOT1L, using specific DOT1LsiRNA also reduced proliferation of lung cancer cells (22). These findings indicate that H3K79 methyltransferase, DOT1L, plays an important role in promoting cancer formation.…”

Section: Discussionmentioning

confidence: 90%

“…In contrast, H3K79 is located in a loop within the globular domain exposed on the nucleosome surface (19). H3K79 methylation by DOT1L (the H3K79 methyltransferase) is frequently correlated with transcriptional activity (16,19) and cancer progression (21,22). For example, DOT1L-regulated H3K79 methylation promotes leukemia formation induced by MLL-AF9 translocations (21).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been reported that aberrant H3K79 methylation by DOT1L occurs in mixed lineage leukemia (MLL) (21). Furthermore, down-regulation of DOT1L results in the inhibition of lung cancer cell proliferation (22). These findings all suggest that DOT1L plays an important role in cancer development.…”

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confidence: 84%

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Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

Bourguignon

Wong

Shiina

2016

Journal of Biological Chemistry

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Human head and neck squamous cell carcinoma is a solid tumor malignancy associated with major morbidity and mortality. In this study, we determined that human head and neck squamous cell carcinoma-derived HSC-3 cells contain a subpopulation of cancer stem cells (CSCs) characterized by a high level of CD44v3 and aldehyde dehydrogenase-1 (ALDH1) expression. Importantly, matrix hyaluronan (HA) induces the up-regulation of stem cell markers that display the hallmark CSC properties. Histone methyltransferase, DOT1L, is also upregulated by HA in CSCs (isolated from HSC-3 cells). Further analyses indicate that the stimulation of microRNA-10b (miR10b) expression is DOT1L-specific and HA/CD44-dependent in CSCs. This process subsequently results in the overexpression of RhoGTPases and survival proteins leading to tumor cell invasion and cisplatin resistance. Treatment of CSCs with DOT1L-specific small interfering RNAs (siRNAs) effectively blocks HA/CD44-mediated expression of DOT1L, miR-10b production, and RhoGTPase/survival protein up-regulation as well as reduces tumor cell invasion and enhances chemosensitivity. CSCs were also transfected with a specific anti-miR-10b inhibitor to silence miR-10b expression and block its target functions. Our results demonstrate that the anti-miR-10 inhibitor not only decreases RhoGTPase/survival protein expression and tumor cell invasion, but also increases chemosensitivity in HA-treated CSCs. Taken together, these findings strongly support the contention that histone methyltransferase, DOT1L-associated epigenetic changes induced by HA play pivotal roles in miR-10 production leading to upregulation of RhoGTPase and survival proteins. All of these events are critically important for the acquisition of cancer stem cell properties, including self-renewal, tumor cell invasion, and chemotherapy resistance in HA/CD44-activated head and neck cancer.Human head and neck squamous cell carcinoma (HNSCC) 2 is a highly malignant cancer associated with major morbidity and mortality (1). A number of studies have identified specific molecules expressed in HNSCC that correlate with tumor behavior. Among such molecules are matrix hyaluronan (HA) (2, 3) and its cell surface receptor, CD44 (4). HA is a major component of the ECM and is significantly enriched in many types of tumors (5). CD44 is a multifunctional transmembrane glycoprotein expressed in HNSCC cells and carcinoma tissues (6, 7). It is commonly expressed as various isoforms generated by alternative mRNA splicing of variant exons inserted into an extracellular membrane-proximal site (8). Most importantly, expression of certain CD44 variant (CD44v) isoforms (especially, CD44v3) is known to be associated with HNSCC progression (6, 9, 10).HNSCC appears to contain a subpopulation of cancer stem cells (CSCs) characterized by a high level of CD44v3 expression (10). In fact, CD44v3 is thought to be one of the important cell surface markers for CSCs (10). These isolated CSCs are capable of generating phenotypically distinct cells resulting in heteroge...

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

Bourguignon

Wong

Shiina

2016

Journal of Biological Chemistry

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“…It was originally identified in yeast where its overexpression led to disruption of telomeric silencing, hence its name [Singer et al 1998]. The H3K79 methylation mark is normally associated with active transcription and H3K79 methylation has been proposed to be a critical histone modification regulating cell proliferation, as its genetic silencing leads to abnormal mitotic spindle formation and cell cycle arrest at the G1 phase [Kim et al 2012b]. DOT1L is known to interact with the phosphorylated C-terminal domain of actively transcribing RNA polymerase II (RNAPII) and through this interaction, DOT1L and subsequent H3K79 methylations are targeted to actively transcribed genes [Kim et al 2012a].…”

Section: Epigenetic Regulators As Promising Therapeutic Targets In Acmentioning

confidence: 99%

Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia

Gallipoli

Giotopoulos

Huntly

2015

Therapeutic Advances in Hematology

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Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is an aggressive hematological malignancy arising in hematopoietic stem and progenitor cells. With the exception of a few specific AML subtypes, the mainstays of treatment have not significantly changed over the last 20 years, and are still based on standard cytotoxic chemotherapy. As a result, clinical outcome remains poor for the majority of patients, with overall long-term survival in the region of 20-30%. Recent successes in characterizing the genetic landscape of AML have highlighted that, despite its heterogeneity, many cases of AML carry recurrent mutations in genes encoding epigenetic regulators. Transcriptional dysregulation and altered epigenetic function have therefore emerged as exciting areas in AML research and it is becoming increasingly clear that epigenetic dysfunction is central to leukemogenesis in AML. This has subsequently paved the way for the development of epigenetically targeted therapies. In this review, we will discuss the most recent advances in our understanding of the role of epigenetic dysregulation in AML pathobiology. We will particularly focus on those altered epigenetic programs that have been shown to be central to the development and maintenance of AML in preclinical models. We will discuss the recent development of therapeutics specifically targeting these key epigenetic programs in AML, describe their mechanism of action and present their current clinical development. Finally, we will discuss the opportunities presented by epigenetically targeted therapy in AML and will highlight future challenges ahead for the AML community, to ensure that these novel therapeutics are optimally translated into clinical practice and result in clinical improvement for AML patients.

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“…It is no surprise, therefore, that histone methylation under the control of several histone methyltransferase (HMT) families has been linked to cell proliferation in models of lung cancer [52]. Indeed, almost 50% of HMTs are associated with tumorigenesis [45].…”

Section: Role Of Histone Modifications In Lung Diseasesmentioning

confidence: 99%

Basic science: Epigenetic programming and the respiratory system

Durham

Adcock

2013

Breathe

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SummaryThe coordinated regulation of gene expression is crucial for survival, especially in multi-cellular organisms. Gene regulation can occur through a number of different mechanisms, which include the binding of transcription factors to gene promoters and enhancers and to gene repressors.Overlaid upon this is the epigenetic (or “above” genetics) regulation of gene expression. Epigenetics has been implicated in the determination of cell differentiation and the control of gene expression by each cell under different external stimuli. Epigenetic mechanisms include DNA methylation, which is principally involved in gene silencing, and plays a key role in maintaining cellular differentiation. Another layer of epigenetic regulation is DNA packaging into chromatin, which can alter the availability of the DNA, and is controlled by histone modifications. Finally non-coding RNAs can also affect the stability of coding mRNA and its ability to interact with ribosomes and be translated into protein.These epigenetic mechanisms are heritable, and maintained through multiple cell divisions, helping to control cell fate, and can even be passed onto germ cells and future generations. In addition to inheritance epigenetics can be altered by the environment, and factors such as pollution and cigarette smoking have been shown to alter the epigenetic profile of cells.The role of epigenetics in controlling gene expression in complex organs, such as the lungs, is a promising area of research and may help to explain complex inheritance patterns and environmental interactions of many lung diseases including asthma, COPD and lung cancer.

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Deficiency of H3K79 Histone Methyltransferase Dot1-like Protein (DOT1L) Inhibits Cell Proliferation

Cited by 117 publications

References 58 publications

Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma

Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia

Basic science: Epigenetic programming and the respiratory system

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