assessment-cellular-bioenergetics-mouse-hematopoietic-stem-primitive

Assessment of Cellular Bioenergetics in Mouse Hematopoietic Stem and Primitive Progenitor Cells using the Extracellular Flux Analyzer

Under steady state, hematopoietic stem cells (HSCs) remain largely quiescent and are believed to be predominantly reliant on glycolysis to meet their ...

University of Michigan, Ann Arbor

In this issue of Cell Chemical Biology, Bowman and colleagues show that the mitochondrial enzyme ACSF3 generates malonyl-CoA from malonate, in turn regulating metabolic flux and mitochondrial protein malonylation (Bowman et al., 2017). The study reveals a mechanism to generate mitochondrial malonyl-CoA and how this molecule impacts mitochondrial biology.

ACSF3 and Mal(onate)-Adapted Mitochondria.

In this issue, Maertens and colleagues demonstrate that HDAC3 inhibition potentiates the effects of MAPK pathway inhibitors in melanoma, including difficult-to-treat - and -driven tumors, with  expression serving as a biomarker for responsiveness to the BRAF/MEK/HDAC inhibitor combination. Mechanistically, this triple cocktail suppresses expression of genes involved in DNA repair, leading to enhanced killing of melanoma cells..

Combined MAPK Pathway and HDAC Inhibition Breaks Melanoma.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas typically developing in the context of neurofibromatosis type 1 (NF-1). With the exception of surgical resection, these tumors are resistant to all current therapies, and unresectable, recurrent, or metastatic tumors are considered incurable. Preclinical studies have identified several novel candidate molecular targets for therapeutic intervention, but, to date, targeted therapies have proven ineffective. Recent studies have identified recurrent mutations in polycomb repressive complex 2 (PRC2) core components, embryonic ectoderm development protein (EED) and suppressor of zeste 12 homolog (SUZ12), in MPNST. These mutations result in global loss of the histone H3 lysine 27 trimethylation epigenetic mark, normally deposited by PRC2, and subsequent gain in acetylation at this residue. This altered chromatin state has been shown to promote MPNST malignancy; however, acetylation at this residue sensitizes MPNSTs to BRD4 and bromodomain and extra-terminal domain inhibition. Interestingly, the catalytic component of PRC2, enhancer of zeste homolog 2 (EZH2), is not mutated in MPNST, hinting that a noncanonical, PRC2-independent function of EZH2 may play a role in this cancer. This review examines the pathobiology of MPNST, the contribution of PRC2 subunits to this process, and the prospects for PRC2-related therapies for this cancer. IMPLICATIONS: Identification of mutations in the PRC2 components EED and SUZ12 in the majority of MPNSTs may imply noncanonical oncogenic activities of the intact component, EZH2, and provide new opportunities for therapeutic intervention.

Malignant Peripheral Nerve Sheath Tumors: From Epigenome to Bedside.

"MPNST Epigenetics"-Response.

Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in , although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.

Article	Year
ACSF3 and Mal(onate)-Adapted Mitochondria. Cell chemical biology\| PubMed ID: 28644952	2017
Combined MAPK Pathway and HDAC Inhibition Breaks Melanoma. Cancer discovery\| PubMed ID: 30936219	2019
Malignant Peripheral Nerve Sheath Tumors: From Epigenome to Bedside. Molecular cancer research : MCR\| PubMed ID: 31023785	2019
"MPNST Epigenetics"-Response. Molecular cancer research : MCR\| PubMed ID: 31575728	2019
High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance. Science advances\| PubMed ID: 33008901	2020
SIRT5's GOT1 up on PDAC. Gastroenterology\| PubMed ID: 34280390	2021

David B. Lombard

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