HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding

Gruber, Joshua J.; Geller, Benjamin; Lipchik, Andrew M.; Chen, Justin; Salahudeen, Ameen A.; Ram, Ashwin N.; Ford, James M.; Kuo, Calvin J.; Snyder, M

doi:10.1016/j.molcel.2019.05.034

Cited by 66 publications

(80 citation statements)

References 65 publications

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“…Cells were taken at different time points and the cell cycle progression was determined by flow cytometry (B) and western blots (C). The expression of Cyclin A begins at late G1 and reaches the maximal level during the G2 phase (54). The level of Cyclin B1 is minimal at G1, increase at S phase and peaks at the G2/M phase (55).…”

Section: Resultsmentioning

confidence: 99%

“…The level of Cyclin B1 is minimal at G1, increase at S phase and peaks at the G2/M phase (55). The expression of Cyclin E1 starts in the middle of the G1 phase and ends at the middle of the S phase (54). Asyn, asynchronized cells.…”

Section: Resultsmentioning

confidence: 99%

“…A recent study by Gruber et al. showed that histone acetyltransferase 1 (HAT1) facilitates GCN5 to acetylate H3K9 to promote histone H4 expression and cell cycle progression (54). Here, we show that H3K9ac promotes histone gene expression and SIRT1 deacetylates H3K9 to repress histone gene expression.…”

Section: Discussionmentioning

confidence: 99%

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Exogenous pyruvate represses histone gene expression and inhibits cancer cell proliferation via the NAMPT–NAD+–SIRT1 pathway

Zhai

et al. 2019

Nucleic Acids Research

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Pyruvate is a glycolytic metabolite used for energy production and macromolecule biosynthesis. However, little is known about its functions in tumorigenesis. Here, we report that exogenous pyruvate inhibits the proliferation of different types of cancer cells. This inhibitory effect of pyruvate on cell growth is primarily attributed to its function as a signal molecule to repress histone gene expression, which leads to less compact chromatin and misregulation of genome-wide gene expression. Pyruvate represses histone gene expression by inducing the expression of NAD+ biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT) via myocyte enhancer factor 2C (MEF2C), which then increases NAD+ levels and activates the histone deacetylase activity of SIRT1. Chromatin immunoprecipitation analysis indicates that pyruvate enhances SIRT1 binding at histone gene promoters where it reduces histone acetylation. Although pyruvate delays cell entry into S phase, pyruvate represses histone gene expression independent of cell cycle progression. Moreover, we find that administration of pyruvate reduces histone expression and retards tumor growth in xenograft mice without significant side effects. Using tissues from cervical and lung cancer patients, we find intracellular pyruvate concentrations inversely correlate with histone protein levels. Together, we uncover a previously unknown function of pyruvate in regulating histone gene expression and cancer cell proliferation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Exogenous pyruvate represses histone gene expression and inhibits cancer cell proliferation via the NAMPT–NAD+–SIRT1 pathway

Zhai

et al. 2019

Nucleic Acids Research

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“…The loss of HAT1 expression leads to the activation of multiple oncogenic signaling pathways in BRAF-mutant melanoma cells HAT1 is a histone acetyltransferase that regulates gene expression 31,32 . Therefore, we speculated that changes in gene expression may underlie the development of BRAFi resistance following reduced HAT1 expression.…”

Section: Hat1 Protein Is Downregulated In Patient-derived Melanoma Samentioning

confidence: 99%

Loss of HAT1 expression confers BRAFV600E inhibitor resistance to melanoma cells by activating MAPK signaling via IGF1R

et al. 2020

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BRAF inhibitors (BRAFi) have been approved for the clinical treatment of BRAF-mutant metastatic melanoma. Although initial responses to BRAFi are generally favorable, acquired BRAFi resistance emerges rapidly, resulting in treatment failure. Only some of the underlying mechanisms responsible for BRAFi resistance are currently understood. Here, we showed that the genetic inhibition of histone acetyltransferase 1 (HAT1) in BRAF-mutant melanoma cells resulted in BRAFi resistance. Using quantitative immunofluorescence analysis of patient sample pairs, consisting of pre-treatment along with matched progressed BRAFi + MEKi-treated melanoma samples, HAT1 downregulation was observed in 7/ 11 progressed samples (~63%) in comparison with pre-treated samples. Employing NanoString-based nCounter PanCancer Pathway Panel-based gene expression analysis, we identified increased MAPK, Ras, transforming growth factor (TGF)-β, and Wnt pathway activation in HAT1 expression inhibited cells. We further found that MAPK pathway activation following the loss of HAT1 expression was partially driven by increased insulin growth factor 1 receptor (IGF1R) signaling. We showed that both MAPK and IGF1R pathway inhibition, using the ERK inhibitor SCH772984 and the IGF1R inhibitor BMS-754807, respectively, restored BRAFi sensitivity in melanoma cells lacking HAT1. Collectively, we show that the loss of HAT1 expression confers acquired BRAFi resistance by activating the MAPK signaling pathway via IGF1R.

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“…The potential regulation of CBP by Hat1 is particularly intriguing given the role of CBP in the acetylation of newly synthesized histone H3 (28). Several reports have suggested that Hat1 is involved in the transcriptional regulation of several genes in different models (29)(30)(31)(32)(33). However, this evidence is conflicted by Hat1's incapacity to acetylate histones in a nucleosome context.…”

Section: Identification Ofmentioning

confidence: 99%

Hat1-Dependent Lysine Acetylation Targets Diverse Cellular Functions

Garcia

Nagarajan

Parthun

2019

Preprint

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Lysine acetylation has emerged as one of the most important post-translational modifications, regulating different biological processes. However, its regulation by lysine acetyltransferases is still unclear in most cases. Hat1 is a lysine acetyltransferase originally identified based on its ability to acetylate histones. Using an unbiased proteomics approach, we have determined how loss of Hat1 affects the mammalian acetylome. Hat1 +/+ and Hat1 -/mouse embryonic fibroblast (MEF) cells lines were grown in both glucose-and galactose-containing media, as Hat1 is required for growth on galactose due to defects in mitochondrial function. Following trypsin digestion of whole cell extracts, acetylated peptides were enriched by acetyllysine affinity purification and acetylated peptides were identified and analyzed by label-free quantitation. Comparison of the acetylome from Hat1 +/+ cells grown on galactose and glucose demonstrated that there are large carbon source-dependent changes in the mammalian acetylome where the acetylation of enzymes involved in glycolysis was the most affected. Comparisons of the acetylomes from Hat1 +/+ and Hat1 -/cells identified 65 proteins whose acetylation decreased by at least 2.5-fold in cells lacking Hat1. In Hat1 -/cells, acetylation of the auto regulatory loop of CBP was the most highly affected, decreasing by up to 20-fold. In addition to proteins involved in chromatin structure, Hat1-dependent acetylation was also found in a number of transcriptional regulators, including p53, and mitochondrial proteins. Hat1 mitochondrial localization suggests that it may be directly involved in the acetylation of mitochondrial proteins.

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HAT1 Coordinates Histone Production and Acetylation via H4 Promoter Binding

Cited by 66 publications

References 65 publications

Exogenous pyruvate represses histone gene expression and inhibits cancer cell proliferation via the NAMPT–NAD+–SIRT1 pathway

Exogenous pyruvate represses histone gene expression and inhibits cancer cell proliferation via the NAMPT–NAD+–SIRT1 pathway

Loss of HAT1 expression confers BRAFV600E inhibitor resistance to melanoma cells by activating MAPK signaling via IGF1R

Hat1-Dependent Lysine Acetylation Targets Diverse Cellular Functions

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