Histone deacetylase 6 in cancer

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Abstract

Histone acetylation and deacetylation are important epigenetic mechanisms that regulate gene expression and transcription. Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family that not only participates in histone acetylation and deacetylation but also targets several nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 (HSP90), to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. Furthermore, HDAC6 also upregulates several critical factors in the immune system, such as program death receptor-1 (PD-1) and program death receptor ligand-1 (PD-L1) receptor, which are the main targets for cancer immunotherapy. Several selective HDAC6 inhibitors are currently in clinical trials for cancer treatment and bring hope for patients with malignant tumors. A fuller understanding of HDAC6 as a critical regulator of many cellular pathways will help further the development of targeted anti-HDAC6 therapies. Here, we review the unique features of HDAC6 and its role in cancer, which make HDAC6 an appealing drug target.

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Most cited references 81

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HDAC family: What are the cancer relevant targets?

Olaf Witt, Hedwig E Deubzer, Till Milde … (2009)

Histone deacetylases comprise a family of 18 genes, which are grouped into classes I-IV based on their homology to their respective yeast orthologues. Classes I, II, and IV consist of 11 family members, which are referred to as "classical" HDACs, whereas the 7 class III members are called sirtuins. Classical HDACs are a promising novel class of anti-cancer drug targets. First HDAC inhibitors have been evaluated in clinical trials and show activity against several cancer diseases. However, these compounds act unselectively against several or all 11 HDAC family members. As a consequence, clinical phase I trials document a wide range of side effects. Therefore, the current challenge in the field is to define the cancer relevant HDAC family member(s) in a given tumor type and to design selective inhibitors, which target cancer cells but leave out normal cells. Knockout of single HDAC family members in mice produces a variety of phenotypes ranging from early embryonic death to viable animals with only discrete alterations, indicating that potential side effects of HDAC inhibitors depend on the selectivity of the compounds. Recently, several studies have shown that certain HDAC family members are aberrantly expressed in several tumors and have non-redundant function in controlling hallmarks of cancer cells. The aim of this review is to discuss individual HDAC family members as drug targets in cancer taking into consideration their function under physiological conditions and their oncogenic potential in malignant disease.

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A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors.

Adeela Kamal, Lia Thao, John Sensintaffar … (2003)

Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signalling proteins, including HER-2/ErbB2, Akt, Raf-1, Bcr-Abl and mutated p53. Hsp90 inhibitors bind to Hsp90, and induce the proteasomal degradation of Hsp90 client proteins. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors selectively kill cancer cells compared to normal cells, and the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is currently in phase I clinical trials. However, the molecular basis of the tumour selectivity of Hsp90 inhibitors is unknown. Here we report that Hsp90 derived from tumour cells has a 100-fold higher binding affinity for 17-AAG than does Hsp90 from normal cells. Tumour Hsp90 is present entirely in multi-chaperone complexes with high ATPase activity, whereas Hsp90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with Hsp90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. These results suggest that tumour cells contain Hsp90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics.

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HDAC6 modulates cell motility by altering the acetylation level of cortactin.

Xiaohong Zhang, Zhigang Yuan, Yingtao Zhang … (2007)

Histone deacetylase 6 (HDAC6) is a tubulin-specific deacetylase that regulates microtubule-dependent cell movement. In this study, we identify the F-actin-binding protein cortactin as a HDAC6 substrate. We demonstrate that HDAC6 binds cortactin and that overexpression of HDAC6 leads to hypoacetylation of cortactin, whereas inhibition of HDAC6 activity leads to cortactin hyperacetylation. HDAC6 alters the ability of cortactin to bind F-actin by modulating a "charge patch" in its repeat region. Introduction of charge-preserving or charge-neutralizing mutations in this cortactin repeat region correlates with the gain or loss of F-actin binding ability, respectively. Cells expressing a charge-neutralizing cortactin mutant were less motile than control cells or cells expressing a charge-preserving mutant. These findings suggest that, in addition to its role in microtubule-dependent cell motility, HDAC6 influences actin-dependent cell motility by altering the acetylation status of cortactin, which, in turn, changes the F-actin binding activity of cortactin.

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Author and article information

Contributors

Jilong Yang: yangjilong@tjmuch.com

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 3 September 2018

Publication date PMC-release: 3 September 2018

Publication date Collection: 2018

Volume: 11

Electronic Location Identifier: 111

Affiliations

[1 ]ISNI 0000 0004 1798 6427, GRID grid.411918.4, Department of Bone and Soft Tissue Tumor, , Tianjin Medical University Cancer Institute and Hospital, ; Tianjin, 300060 People’s Republic of China

[2 ]ISNI 0000 0004 1798 6427, GRID grid.411918.4, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, , Tianjin Medical University Cancer Institute and Hospital, ; Tianjin, 300060 People’s Republic of China

[3 ]ISNI 0000 0000 9792 1228, GRID grid.265021.2, International Medical School, , Tianjin Medical University, ; Tianjin, 300061 People’s Republic of China

[4 ]ISNI 0000 0004 1798 6427, GRID grid.411918.4, Department of Epidemiology and Biostatistics, , Tianjin Medical University Cancer Institute and Hospital, ; Tianjin, 300060 People’s Republic of China

[5 ]ISNI 0000 0001 2185 3318, GRID grid.241167.7, Cancer Genomics and Precision Medicine, , Wake Forest Baptist Comprehensive Cancer Center, ; Winston-Salem, NC USA

Article

Publisher ID: 654

DOI: 10.1186/s13045-018-0654-9

PMC ID: 6122547

PubMed ID: 30176876

SO-VID: 386eee6b-d4a4-4d69-a574-c983be631f6f

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 10 July 2018

Date accepted : 22 August 2018

Funding

Funded by: National Nature Science Foundation of China

Award ID: 81372872

Award ID: 81402215

Award ID: 81320108022

Award Recipient : Jilong Yang

Funded by: Nature Science Foundation of Tianjin

Award ID: 16JCYBJC24100

Award Recipient : Jilong Yang

Funded by: Innovative University Research Teams in China

Award ID: IRT_14R40

Award Recipient : Jilong Yang

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hdac6,pd-1/pd-l1,α-tubulin,hsp90,cortactin,target therapy

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hdac6, pd-1/pd-l1, α-tubulin, hsp90, cortactin, target therapy

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Histone deacetylase 6 in cancer

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Karger: Oncology

Most cited references 81

HDAC family: What are the cancer relevant targets?

A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors.

HDAC6 modulates cell motility by altering the acetylation level of cortactin.

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