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HDAC6: A unique HDAC family member as a cancer target

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Abstract

Background

HDAC6, a structurally and functionally distinct member of the HDAC family, is an integral part of multiple cellular functions such as cell proliferation, apoptosis, senescence, DNA damage and genomic stability, all of which when deregulated contribute to carcinogenesis. Among several HDAC family members known so far, HDAC6 holds a unique position. It differs from the other HDAC family members not only in terms of its subcellular localization, but also in terms of its substrate repertoire and hence cellular functions. Recent findings have considerably expanded the research related to the substrate pool, biological functions and regulation of HDAC6. Studies in HDAC6 knockout mice highlighted the importance of HDAC6 as a cell survival player in stressful situations, making it an important anticancer target. There is ample evidence stressing the importance of HDAC6 as an anti-cancer synergistic partner of many chemotherapeutic drugs. HDAC6 inhibitors have been found to enhance the effectiveness of conventional chemotherapeutic drugs such as DNA damaging agents, proteasome inhibitors and microtubule inhibitors, thereby highlighting the importance of combination therapies involving HDAC6 inhibitors and other anti-cancer agents.

Conclusions

Here, we present a review on HDAC6 with emphasis on its role as a critical regulator of specific physiological cellular pathways which when deregulated contribute to tumorigenesis, thereby highlighting the importance of HDAC6 inhibitors as important anticancer agents alone and in combination with other chemotherapeutic drugs. We also discuss the synergistic anticancer effect of combination therapies of HDAC6 inhibitors with conventional chemotherapeutic drugs.

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Abbreviations

αTAT:

α Tubulin acetyltransferases

ADR:

Adriamycin

Adv:

Adavosertib

ALCL:

Anaplastic large cell lymphoma

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

AR:

Androgen receptor

BTK:

Bruton's tyrosine kinase

BTZ:

Bortezomib

CBP:

CREB-binding protein

CC:

Cholangiocarcinoma

CDK1:

Cyclin-dependent kinase 1

CDKi:

Cyclin-dependent kinase inhibitor

CRD-1:

Cell cycle regulatory domain 1

CHK:

Checkpoint kinase

CLL:

Chronic Lymphoid Leukemia

COX-2:

Cyclooxygenase– 2

CYLD:

Cylindromatosis

DHT:

Dihydrotestosterone

DLBCL:

Diffuse large B cell lymphoma

ECs:

Endothelial cells

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

ER:

Estrogen Receptor

ERKs:

Extracellular signal-regulated kinases

FOXP3:

Forkhead boxp3

GC:

Gynecological cancer

Gli1:

Glioma-associated oncogene homolog 1

GPCRs:

G protein coupled receptors

GR:

Glucocorticoid receptor

GRK2:

G protein-coupled receptor kinase

GRP:

Glucose-regulated protein

GSCs:

Glioma stem cells

GSK3b:

Glycogen synthase kinase 3

G3BP1:

GTPase activating protein SH3 domain binding protein 1

HATs:

Histone acetyltransferases

HCC:

Hepatocellular carcinoma

HDAC6i:

HDAC6 inhibitors

HDACs:

Histone deacetylases

HEK:

Human embryonic kidney cells

HIF-1:

Hypoxia-inducible factor

HO-1:

Hemeoxygenase 1

HSF1:

Heat-shock factor 1

Hsp90:

Heat shock protein 90

IBC:

Inflammatory breast cancer

IIp:

Invasion inhibitory protein

IMiDs:

Immunomodulatory drugs

MAPK:

Microtubule associated protein kinase

MBC:

Metastatic breast cancer

MCL:

Mantle cell lymphoma

MEFs:

Mouse embryonic fibroblast

MLH1:

MutL homolog 1

MM:

Multiple myeloma

MMP9:

Matrix metallopeptidase 9

MMR:

Mismatch repair

MPT0G413:

N-hydroxy-4-((5-(4-methoxybenzoyl)- 1H-indol-1-yl)methyl)benzamide

MSCs:

Mesenchymal stem cells

MT:

Microtubule

MTOC:

Microtubule-organizing center

Mtor:

Mammalian target of rapamycin

NAD:

Nicotinamide adenine dinucleotide

NES:

Nuclear export signal

NHL:

Non-Hodgkin lymphoma

NLS:

Nuclear localization signal

Nrf-2:

Nuclear factor erythroid 2–related factor 2

NSCLC:

Non-Small Cell Lung Cancer

PCAF:

p300/CBP associated factor

PDGF:

Platelet-derived growth factor

PI3K:

Phosphoinositide 3-kinases

Pkc:

Protein kinase C

PKCz:

Protein kinase C isoform z

PrEC:

Prostate epithelial cells

PTEN:

Phosphatase and tensin homolog

PTPN1:

Tyrosine-protein phosphatase non-receptor type 1

RMS:

Rhabdomyosarcoma

ROCK:

Rho-associated coiled-coil kinase

ROS:

Reactive oxygen species

RUNX2:

Runt-related transcription factor 2

SAHA:

Suberoylanilidehydroxamic acid

SIRT:

Sirtuins

TMZ:

Temozolomide

TPPP/p25:

Tubulin polymerization-promoting protein/p25

UPR:

Unfolded protein response

VEGF:

Vascular endothelial growth factor

XIAP:

X-linked inhibitor of apoptosis

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Funding

Sumeet Kaur would like to thank the University Grants Commission (UGC), New Delhi, India, for awarding her a UGC fellowship. Prerna Rajoria would like to thank the Department of Biotechnology (DBT), Ministry of Science & Technology, Government of India for awarding her a DBT-JRF fellowship (Grant Number: DBT/2021–22/CBR/1593).

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  1. Laboratory of Molecular Modeling and Anticancer Drug Development, Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India

    Sumeet Kaur, Prerna Rajoria & Madhu Chopra

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  1. Sumeet Kaur
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  2. Prerna Rajoria
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  3. Madhu Chopra
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Madhu Chopra conceptualized the article and critically revised the work. Sumeet Kaur conceptualized the article, performed the literature search, and drafted and critically revised the work. Prerna Rajoria performed the literature search and prepared the figures.

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Correspondence to Madhu Chopra.

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Kaur, S., Rajoria, P. & Chopra, M. HDAC6: A unique HDAC family member as a cancer target. Cell Oncol. 45, 779–829 (2022). https://doi.org/10.1007/s13402-022-00704-6

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