Multiple Screening Approaches Reveal HDAC6 As a Novel Regulator of Glycolytic Metabolism in Triple-negative Breast Cancer

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Feb 1

PMID 33523897

Citations 25

Authors

Catriona M Dowling

Kate E R Hollinshead

Alessandra Di Grande

Justin Pritchard

Hua Zhang

Eugene T Dillon

Kathryn Haley

Eleni Papadopoulos

Anita K Mehta

Rachel Bleach

Andreas U Lindner

Brian Mooney

Heiko Dussmann

Darran OConnor

Jochen H M Prehn

Kieran Wynne

Michael Hemann

James E Bradner

Alec C Kimmelman

Jennifer L Guerriero

Gerard Cagney

Kwok-Kin Wong

Anthony G Letai

Triona Ni Chonghaile

Affiliations

Soon will be listed here.

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TNBC cells that were independent of mitochondrial apoptosis. Using a functional genetic approach, we identified that a "hit" compound, BAS-2, had a potentially similar mechanism of action to histone deacetylase inhibitors (HDAC). An in vitro HDAC inhibitor assay confirmed that the compound selectively inhibited HDAC6. Using state-of-the-art acetylome mass spectrometry, we identified glycolytic substrates of HDAC6 in TNBC cells. We confirmed that inhibition or knockout of HDAC6 reduced glycolytic metabolism both in vitro and in vivo. Through a series of unbiased screening approaches, we have identified a previously unidentified role for HDAC6 in regulating glycolytic metabolism.

Citing Articles

Potentiation of immune checkpoint blockade with a pH-sensitizer as monitored in two pre-clinical tumor models with acidoCEST MRI.

Tran R, Li T, de la Cerda J, Schuler F, Khaled A, Pudakalakatti S Br J Cancer. 2025; .

PMID: 39994445 DOI: 10.1038/s41416-025-02962-1.

Regulation of HDAC6 Catalytic Activity in Cancer: The Role of Post-Translational Modifications and Protein-Protein Interactions.

Asaad L, Pepperrell B, McErlean E, Furlong F Int J Mol Sci. 2025; 26(3).

PMID: 39941046 PMC: 11818932. DOI: 10.3390/ijms26031274.

Temporal regulation of acetylation status determines PARP1 role in DNA damage response and metabolic homeostasis.

Tyagi W, Das S Sci Adv. 2024; 10(42):eado7720.

PMID: 39423262 PMC: 11488539. DOI: 10.1126/sciadv.ado7720.

Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer.

Lu B, Qiu R, Wei J, Wang L, Zhang Q, Li M Nat Cancer. 2024; 5(11):1622-1640.

PMID: 39198689 DOI: 10.1038/s43018-024-00816-y.

Apigenin and its combination with Vorinostat induces apoptotic-mediated cell death in TNBC by modulating the epigenetic and apoptotic regulators and related miRNAs.

Nimal S, Kumbhar N, Saruchi , Rathore S, Naik N, Paymal S Sci Rep. 2024; 14(1):9540.

PMID: 38664447 PMC: 11045774. DOI: 10.1038/s41598-024-60395-x.

References

Lewis C, Parker S, Fiske B, McCloskey D, Gui D, Green C . Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol Cell. 2014; 55(2):253-63. PMC: 4106038. DOI: 10.1016/j.molcel.2014.05.008. View

Davidson S, Papagiannakopoulos T, Olenchock B, Heyman J, Keibler M, Luengo A . Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer. Cell Metab. 2016; 23(3):517-28. PMC: 4785096. DOI: 10.1016/j.cmet.2016.01.007. View

Wardell S, Ilkayeva O, Wieman H, Frigo D, Rathmell J, Newgard C . Glucose metabolism as a target of histone deacetylase inhibitors. Mol Endocrinol. 2008; 23(3):388-401. PMC: 2654518. DOI: 10.1210/me.2008-0179. View

Morris A, Tolan D . Lysine-146 of rabbit muscle aldolase is essential for cleavage and condensation of the C3-C4 bond of fructose 1,6-bis(phosphate). Biochemistry. 1994; 33(40):12291-7. DOI: 10.1021/bi00206a036. View

Yang W, Stockwell B . Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol. 2008; 15(3):234-45. PMC: 2683762. DOI: 10.1016/j.chembiol.2008.02.010. View

Warburg O . On respiratory impairment in cancer cells. Science. 1956; 124(3215):269-70. View

Balko J, Giltnane J, Wang K, Schwarz L, Young C, Cook R . Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 2013; 4(2):232-45. PMC: 3946308. DOI: 10.1158/2159-8290.CD-13-0286. View

Liedtke C, Mazouni C, Hess K, Andre F, Tordai A, Mejia J . Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008; 26(8):1275-81. DOI: 10.1200/JCO.2007.14.4147. View

Wang X, Wan R, Liu Z . Recent advances in the discovery of potent and selective HDAC6 inhibitors. Eur J Med Chem. 2017; 143:1406-1418. DOI: 10.1016/j.ejmech.2017.10.040. View

10.

Fernandez C, Des Rosiers C, Previs S, David F, Brunengraber H . Correction of 13C mass isotopomer distributions for natural stable isotope abundance. J Mass Spectrom. 1996; 31(3):255-62. DOI: 10.1002/(SICI)1096-9888(199603)31:3<255::AID-JMS290>3.0.CO;2-3. View

11.

Elenbaas B, Spirio L, Koerner F, Fleming M, Zimonjic D, Donaher J . Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev. 2001; 15(1):50-65. PMC: 312602. DOI: 10.1101/gad.828901. View

12.

Chonghaile T, Sarosiek K, Vo T, Ryan J, Tammareddi A, Gaizo Moore V . Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy. Science. 2011; 334(6059):1129-33. PMC: 3280949. DOI: 10.1126/science.1206727. View

13.

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

14.

Li F, Huang Q, Luster T, Hu H, Zhang H, Ng W . Epigenetic CRISPR Screen Identifies as an Immunotherapeutic Target in -Mutant Lung Adenocarcinoma. Cancer Discov. 2019; 10(2):270-287. PMC: 7007372. DOI: 10.1158/2159-8290.CD-19-0780. View

15.

Zordoky B, Bark D, Soltys C, Sung M, Dyck J . The anti-proliferative effect of metformin in triple-negative MDA-MB-231 breast cancer cells is highly dependent on glucose concentration: implications for cancer therapy and prevention. Biochim Biophys Acta. 2014; 1840(6):1943-57. DOI: 10.1016/j.bbagen.2014.01.023. View

16.

Shalem O, Sanjana N, Hartenian E, Shi X, Scott D, Mikkelson T . Genome-scale CRISPR-Cas9 knockout screening in human cells. Science. 2013; 343(6166):84-87. PMC: 4089965. DOI: 10.1126/science.1247005. View

17.

Metallo C, Gameiro P, Bell E, Mattaini K, Yang J, Hiller K . Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2011; 481(7381):380-4. PMC: 3710581. DOI: 10.1038/nature10602. View

18.

Hook S, Orian A, Cowley S, Eisenman R . Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. Proc Natl Acad Sci U S A. 2002; 99(21):13425-30. PMC: 129689. DOI: 10.1073/pnas.172511699. View

19.

Pelicano H, Zhang W, Liu J, Hammoudi N, Dai J, Xu R . Mitochondrial dysfunction in some triple-negative breast cancer cell lines: role of mTOR pathway and therapeutic potential. Breast Cancer Res. 2014; 16(5):434. PMC: 4303115. DOI: 10.1186/s13058-014-0434-6. View

20.

Hallows W, Yu W, Denu J . Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem. 2011; 287(6):3850-8. PMC: 3281715. DOI: 10.1074/jbc.M111.317404. View