Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer

Dowling, Catríona M.; Hollinshead, Kate E.R.; Grande, Alessandra Di; Pritchard, Justin R.; Zhang, Hua; Dillon, Eugene; Haley, Kathryn E.; Papadopoulos, Eleni; Mehta, Anita K.; Bleach, Rachel; Lindner, Andreas U.; Mooney, Brian; Düßmann, Heiko; O’Connor, Darran P.; Prehn, Jochen H M; Wynne, Kieran; Hemann, Michael T.; Bradner, James E.; Kimmelman, Alec C.; Guerriero, Jennifer L.; Cagney, Gerard; Wong, Kwok-Kin; Letaï, Anthony; Chonghaile, Tríona Ní

doi:10.1126/sciadv.abc4897

Cited by 50 publications

(26 citation statements)

References 57 publications

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“…Recently, a new interaction between the key redox metabolite NADPH and HDAC3 was discovered in adipocytes [64]. Novel high throughput functional genomics screening methods have identified HDAC6 as a regulator of glycolysis [65]. It is likely that there are several other metabolites like NADPH that may moonlight and play an epigenetic role.…”

Section: Discussionmentioning

confidence: 99%

Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

2021

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Histone deacetylases (HDACs) are epigenetic enzymes that play a central role in gene regulation and are sensitive to the metabolic state of the cell. The cross talk between metabolism and histone acetylation impacts numerous biological processes including development and immune function. HDAC inhibitors are being explored for treating cancers, viral infections, inflammation, neurodegenerative diseases, and metabolic disorders. However, how HDAC inhibitors impact cellular metabolism and how metabolism influences their potency is unclear. Discussed herein are recent applications and future potential of systems biology methods such as high throughput drug screens, cancer cell line profiling, single cell sequencing, proteomics, metabolomics, and computational modeling to uncover the interplay between metabolism, HDACs, and HDAC inhibitors. The synthesis of new systems technologies can ultimately help identify epigenomic and metabolic biomarkers for patient stratification and the design of effective therapeutics.

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Section: Discussionmentioning

confidence: 99%

Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

2021

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“…Removal of the acetyl group induces oligomerization and activation of GLS which reduces oxidative stress in cancer cells therefore promoting their survival 70 . Glycolytic enzymes have been proposed to be substrates of HDAC6 71 , and our acetylome screen identified two glycolytic enzymes shown to interact with HDAC6, phosphoglycerate kinase 1 (PGK1) 72 and pyruvate kinase muscle (PKM) 73 . The acetylome screen identified additional metabolic enzymes, including heme oxygenase 1 (HMOX1) 74 , ATP-citrate lyase (ACLY) 56 , and malic enzyme 1 (ME1) 75 .…”

Section: Discussionmentioning

confidence: 99%

Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates

Jk¹,

Diffley

et al. 2021

Preprint

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Histone deacetylases play important biological roles well beyond the deacetylation of histone tails, and therefore have recently been renamed to acetyl-lysine deacetylases (KDACs). In particular, KDAC6 is involved in multiple cellular processes such as apoptosis, cytoskeleton reorganization, and protein folding, affecting substrates such as α-tubulin, Hsp90 and cortactin proteins. We have applied a biochemical enzymatic assay to measure the activity of KDAC6 on a set of candidate unlabeled peptides. These served for the calibration of a structure-based substrate prediction protocol, Rosetta FlexPepBind, previously used for the successful substrate prediction of KDAC8 and other enzymes. The calibration process and comparison of the results between KDAC6 and KDAC8 highlighted structural differences that explain the already reported promiscuity of KDAC6. A proteome-wide screen of reported acetylation sites using our calibrated protocol together with the enzymatic assay provide new peptide substrates and avenues to novel potential functional regulatory roles of this promiscuous, multi-faceted enzyme.

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“…The results of the second-phase clinical study show that FK228 can effectively control T-cell lymphoma, with safety and reliability (NCT00426764, NCT00106431) (Table 2) (Foss et al, 2014;Foss et al, 2016). The HDAC inhibitor BAS-2 inhibits HDAC6, affects the ENO1 gene and LDHA related to glucose metabolism, and ultimately affects glycolysis in breast cancer (Dowling et al, 2021). Studies have shown that 1A12 can inhibit the acetylation level of histone H3, and it can also affect the glucose metabolism level in preclinical test subjects (Chan et al, 2014).…”

Section: Clinical Trialsmentioning

confidence: 99%

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

Huo

Zhang

Huang

et al. 2021

Front. Cell Dev. Biol.

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Epigenetic modifications and metabolism are two fundamental biological processes. During tumorigenesis and cancer development both epigenetic and metabolic alterations occur and are often intertwined together. Epigenetic modifications contribute to metabolic reprogramming by modifying the transcriptional regulation of metabolic enzymes, which is crucial for glucose metabolism, lipid metabolism, and amino acid metabolism. Metabolites provide substrates for epigenetic modifications, including histone modification (methylation, acetylation, and phosphorylation), DNA and RNA methylation and non-coding RNAs. Simultaneously, some metabolites can also serve as substrates for nonhistone post-translational modifications that have an impact on the development of tumors. And metabolic enzymes also regulate epigenetic modifications independent of their metabolites. In addition, metabolites produced by gut microbiota influence host metabolism. Understanding the crosstalk among metabolism, epigenetic modifications, and gene expression in cancer may help researchers explore the mechanisms of carcinogenesis and progression to metastasis, thereby provide strategies for the prevention and therapy of cancer. In this review, we summarize the progress in the understanding of the interactions between cancer metabolism and epigenetics.

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Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer

Cited by 50 publications

References 57 publications

Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

Metabolism, HDACs, and HDAC Inhibitors: A Systems Biology Perspective

Structure-based prediction of HDAC6 substrates validated by enzymatic assay reveals determinants of promiscuity and detects new potential substrates

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

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