An Achilles' Heel for MLL-Rearranged Leukemias: Writers and Readers of H3 Lysine 36 Dimethylation

Balbach, Sebastian T.; Orkin, Stuart H.

doi:10.1158/2159-8290.cd-16-0564

Cited by 6 publications

(5 citation statements)

References 11 publications

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“…The same difficulties in establishing causal links apply also in this setting. In that respect exploring metabolic dependencies in settings where a genetic lesion modifies chromatin as in MLL-rearranged leukemias 125, 126 , or pediatric brain tumors and sarcomas with histone mutations 127, 128 , might prove fruitful as these cases could be particularly susceptible to a disruption in metabolism.…”

Section: Future Directionsmentioning

confidence: 99%

The impact of cellular metabolism on chromatin dynamics and epigenetics

2017

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The substrates used to modify nucleic acids and chromatin are affected by nutrient availability and the activity of metabolic pathways. Thus, cellular metabolism constitutes a fundamental component of chromatin status and thereby of genome regulation. Here we describe the biochemical and genetic principles of how metabolism can influence chromatin biology and epigenetics, discuss the functional roles of this interplay in developmental and cancer biology, and present future directions in this rapidly emerging area.

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Section: Future Directionsmentioning

confidence: 99%

The impact of cellular metabolism on chromatin dynamics and epigenetics

2017

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“…ASH1L is a histone methyltransferase which belongs to a group of transcriptional activating proteins [8]. Although the pathological functions of ASH1L in the development of different types of cancer have been reported [15], our current RNAseq analysis provides invaluable insights in identifying the genes modulated by ASH1L in HCC. Further investigation dissecting the precise pathological role of ASH1L and its corresponding molecular mechanisms in HCC development is warranted.…”

Section: Discussionmentioning

confidence: 99%

“…ASH1L has been implicated in the development of different types of cancers [15]. For example, it is ampli ed in lung cancer cell lines and can promote lung cancer metastasis through the CDK5/P35 pathway[16] [17].…”

Section: Introductionmentioning

confidence: 99%

Increase of ASH1L Expression Promotes Hepatocellular Carcinoma Development and Affects the Prognosis of Liver Transplantation Patients

Zhang

Xiang

et al. 2023

Preprint

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Hepatocellular carcinoma (HCC) is a prevalent malignancy worldwide, characterized by high morbidity and mortality rates. Risk factors associated with HCC include cirrhosis, alcohol abuse, metabolic syndrome, hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection. Unfortunately, the cure rate of HCC remains low, primarily due to difficulties in early-stage detection. The identification of effective therapeutic targets and novel biomarkers is thus imperative. However, the precise molecular mechanisms underlying HCC development remain elusive. Recent studies have indicated a significant correlation between DNA methylation and cancer development. Notably, bioinformatics analysis of human patient databases has revealed amplification of ASH1L, a histone methyltransferase and a homolog of drosophila ASH1, in tumor tissues. Alterations in ASH1L expression have been implicated in the pathogenesis of various diseases, including prostate cancer, lung cancer, uterine cancer, and leukemia. Its molecular mechanism and cellular functions are undergone extensive studies. Specifically, investigating the role of ASH1L in HCC development represents a promising avenue for understanding the underlying mechanisms. Building upon these backgrounds and considerations, this study aims to elucidate the detrimental effects of ASH1L on the prognosis of HCC patients following liver transplantation, as well as the potential underlying mechanisms. With using various approaches, ASH1L was found to be strongly correlated with HCC. Furthermore, ASH1L shows promise as a potential biomarker for early detection, prognosis prediction, and personalized treatment strategies for HCC.

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“…TGFb stimulation in NI-HBE cells increased H3K36me2 and H3K4me3, but not H3K27me2 or H3K9me2 levels at the p21 promoter region covering p53RE ( Supplementary Fig. S5A), while only H3K36me2 accumulation, which is associated with transcriptional activation (35), was apparently blocked by rFH T90Aor rFH R233H expression in TGFb-treated NI-HBE cells (Supplementary Fig. S5B).…”

Section: Local Fumarate Maintains H3k36me2 Through Inhibition Of Kdm2mentioning

confidence: 97%

PAK4 Phosphorylates Fumarase and Blocks TGFβ-Induced Cell Growth Arrest in Lung Cancer Cells

et al. 2019

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The metabolic activity of fumarase (FH) participates in gene transcription linking to tumor cell growth. However, whether this effect is implicated in lung cancer remains unclear. Here, we show TGFb induces p38-mediated FH phosphorylation at Thr 90, which leads to a FH/CSL (also known as RBP-Jk)/p53 complex formation and FH accumulation at p21 promoter under concomitant activation of Notch signaling; in turn, FH inhibits histone H3 Lys 36 demethylation and thereby promotes p21 transcription and cell growth arrest. In addition, FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation. Physiologically, FH Ser 46 phosphorylation promotes tumorigenesis through its suppressive effect on FH Thr 90 phosphorylation-mediated cell growth arrest in NSCLC cells and correlates with poor prognosis in patients with lung cancer. Our findings uncover an uncharacterized mechanism underlying the local effect of FH on TGFb-induced gene transcription, on which the inhibitory effect from PAK4 promotes tumorigenesis in lung cancer. Significance: Fumarase counteracts CSL via its metabolic activity to facilitate TGFb-induced cell growth arrest, an effect largely blocked by PAK4-mediated phosphorylation of fumarase.

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An Achilles' Heel for MLL-Rearranged Leukemias: Writers and Readers of H3 Lysine 36 Dimethylation

Cited by 6 publications

References 11 publications

The impact of cellular metabolism on chromatin dynamics and epigenetics

The impact of cellular metabolism on chromatin dynamics and epigenetics

Increase of ASH1L Expression Promotes Hepatocellular Carcinoma Development and Affects the Prognosis of Liver Transplantation Patients

PAK4 Phosphorylates Fumarase and Blocks TGFβ-Induced Cell Growth Arrest in Lung Cancer Cells

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