DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling

Ishiguro, Kazuya; Kitajima, Hiroshi; Niinuma, Takeshi; Ishida, Tadao; Maruyama, Reo; Ikeda, Hiroshi; Hayashi, Toshiaki; Sasaki, Hajime; Wakasugi, Hideki; Nishiyama, Koyo; Shindo, Tetsuya; Yamamoto, Eiko; Kai, Masahiro; Sasaki, Yasushi; Tokino, Takashi; Nakase, Hiroshi; Suzuki, Hiromu

doi:10.3324/haematol.2018.191262

Cited by 30 publications

(31 citation statements)

References 43 publications

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“…Importantly, H3K79me2 was enriched on the − 6682~+ 284 region of c-Myc promoter in both SW480 and HCT116 cells. Actually, a recent study also reported that DOT1L could transcriptionally activate c-Myc expression in multiple myeloma [74]. Our data showed the detailed mechanism of epigenetic regulation of c-Myc in CRC cells.…”

Section: Discussionsupporting

confidence: 60%

Silencing or inhibition of H3K79 methyltransferase DOT1L induces cell cycle arrest by epigenetically modulating c-Myc expression in colorectal cancer

et al. 2019

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Background: Epigenetic regulations play pivotal roles in tumorigenesis and cancer development. Disruptor of telomeric silencing-1-like (DOT1L), also known as KMT4, is the only identified histone methyltransferase that catalyzes the mono-, di-, and tri-methylation of lysine 79 histone 3 (H3K79). However, little is known about the effect of H3K79 methylation on the modulation of colorectal cancer (CRC) development. Methods: DOT1L expression profiles in different subgroups of CRC tissues and its clinical significances were analyzed from some online datasheets. DOT1L in CRC cell lines was silenced by either lentivirus-mediated knockdown or inhibited by its specific inhibitor, EPZ004777. Then cell proliferation was detected by MTT assay, BrdU assay, and soft agar assay; cell cycle was detected by cytometry; and tumorigenicity was detected by using nude mice xenograft models. Clinical co-expression was analyzed between DOT1L and c-Myc. Chromatin immunoprecipitation (ChIP) assay was used to determine whether the translation of c-Myc was epigenetically regulated by H3K79me2 induced by DOT1L. c-Myc overexpression was used to rescue the cell cycle arrest and tumor growth induced by DOT1L silencing or inhibition in CRC.Results: We found that DOT1L was highly expressed in colorectal cancer and was negatively related to the prognosis of patients with CRC. Silencing or inhibition of DOT1L blocked cell proliferation, BrdU incorporation, selfrenewal capability in vitro, and tumorigenicity in vivo. Besides, inhibition or silencing of DOT1L also induced cell cycle arrest at S phase, as well as decreased the expression of CDK2 and Cyclin A2. Furthermore, in the clinical databases of CRC, we found that the expression of DOT1L was positively correlated with that of c-Myc, a major regulator in the upstream of cell cycle-related factors. Besides, c-Myc expression was downregulated after DOT1L knockdown and c-Myc restoration rescued decrease of cell proliferation, BrdU corporation, self-renewal capability, cell cycle progression in vitro and tumorigenicity in vivo induced by DOT1L silencing. Then we found that H3K79 methylation was decreased after DOT1L knockdown. ChIP assay showed that H3K79me2 was enriched on the -682~+ 284 region of c-Myc promoter, and the enrichment was decreased after DOT1L inhibition. Conclusions: Our results show that DOT1L epigenetically promotes the transcription of c-Myc via H3K79me2. DOT1L silencing or inhibition induces cell cycle arrest at S phase. DOT1L is a potential marker for colorectal cancer and EPZ004777 may be a potential drug for the treatment of colorectal cancer.

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Section: Discussionsupporting

confidence: 60%

Silencing or inhibition of H3K79 methyltransferase DOT1L induces cell cycle arrest by epigenetically modulating c-Myc expression in colorectal cancer

et al. 2019

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“…We find that modulation of Dot1L-DE genes does not substitute for Dot1L chemical inhibition (Fig 4) suggesting that H3K79me may have a role in reprogramming beyond transcriptional regulation of single genes. Transcriptome-wide studies with Dot1L depletion or chemical inhibition in other paradigms have also revealed that few genes are affected by loss of H3K79me (Barry et al, 2009;Ho et al, 2013;Ishiguro et al, 2019), despite its enrichment at thousands of genes (Fig 2) (Chronis et al, 2017). For example, only four genes, were differentially expressed in Dot1L KO mouse c-kit+ cells sorted from E10.5 yolk sacs where profound phenotypic alterations in vascular morphology and erythrocyte maturation were observed (Feng et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Dot1L methyltransferase activity is a barrier to acquisition of pluripotency but not transdifferentiation

Wille

Sridharan

2019

Preprint

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Pluripotent stem cells (PSCs) exist in a unique state poised to differentiate into any of the somatic cell types in part by maintaining an open chromatin structure. How these extraordinary cells suppress spurious transcription in the relative absence of repressive epigenetic modifications is poorly understood. PSCs are depleted for transcriptional elongation associated epigenetic modifications, primarily H3K79me2. Although H3K79me2 is found on thousands of genes, inhibiting the enzymatic activity of its methyltransferase, Dot1L results in few transcriptional changes, the majority of which are upregulated. During reprogramming of somatic cells to pluripotency, Dot1L inhibition (Dot1Li) at the midpoint is particularly effective at yielding greater number of colonies. Further, Dot1Li enhances reprogramming beyond early phases such as the mesenchymal to epithelial transition and from already epithelial cell types such as keratinocytes. Modulation of single genes from the DotLi transcriptional response cannot replace its function. Significantly, Dot1L inhibition does not enhance lineage conversion to neurons. Taken together, our results indicate that H3K79me is not a universal barrier of cell fate transitions but specifically protects cells from reverting to the pluripotent state.

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“…Previous studies have uncovered an important role for DOT1L in driving pathogenesis of acute myeloid leukemias (AML) with mixed lineage leukemia (MLL) gene translocations 4 , 9 . Other studies have demonstrated the efficacy of DOT1L inhibition in solid tumors 10 – 13 , however its role in prostate cancer (PCa) is yet to be delineated. PCa is the most common adult malignancy in men and the second most lethal 14 .…”

Section: Introductionmentioning

confidence: 99%

Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer

et al. 2020

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The histone methyltransferase DOT1L methylates lysine 79 (K79) on histone H3 and is involved in Mixed Lineage Leukemia (MLL) fusion leukemogenesis; however, its role in prostate cancer (PCa) is undefined. Here we show that DOT1L is overexpressed in PCa and is associated with poor outcome. Genetic and chemical inhibition of DOT1L selectively impaired the viability of androgen receptor (AR)-positive PCa cells and organoids, including castration-resistant and enzalutamide-resistant cells. The sensitivity of AR-positive cells is due to a distal K79 methylation-marked enhancer in the MYC gene bound by AR and DOT1L not present in AR-negative cells. DOT1L inhibition leads to reduced MYC expression and upregulation of MYC-regulated E3 ubiquitin ligases HECTD4 and MYCBP2, which promote AR and MYC degradation. This leads to further repression of MYC in a negative feed forward manner. Thus DOT1L selectively regulates the tumorigenicity of AR-positive prostate cancer cells and is a promising therapeutic target for PCa.

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DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling

Cited by 30 publications

References 43 publications

Silencing or inhibition of H3K79 methyltransferase DOT1L induces cell cycle arrest by epigenetically modulating c-Myc expression in colorectal cancer

Silencing or inhibition of H3K79 methyltransferase DOT1L induces cell cycle arrest by epigenetically modulating c-Myc expression in colorectal cancer

Dot1L methyltransferase activity is a barrier to acquisition of pluripotency but not transdifferentiation

Histone methyltransferase DOT1L coordinates AR and MYC stability in prostate cancer

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