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The role of deubiquitinating enzymes in cancer drug resistance

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Abstract

Drug resistance is a well-known phenomenon leading to a reduction in the effectiveness of pharmaceutical treatments. Resistance to chemotherapeutic agents can involve various intrinsic cellular processes including drug efflux, increased resistance to apoptosis, increased DNA damage repair capabilities in response to platinum salts or other DNA-damaging drugs, drug inactivation, drug target alteration, epithelial–mesenchymal transition (EMT), inherent cell heterogeneity, epigenetic effects, or any combination of these mechanisms. Deubiquitinating enzymes (DUBs) reverse ubiquitination of target proteins, maintaining a balance between ubiquitination and deubiquitination of proteins to maintain cell homeostasis. Increasing evidence supports an association of altered DUB activity with development of several cancers. Thus, DUBs are promising candidates for targeted drug development. In this review, we outline the involvement of DUBs, particularly ubiquitin-specific proteases, and their roles in drug resistance in different types of cancer. We also review potential small molecule DUB inhibitors that can be used as drugs for cancer treatment.

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Abbreviations

USP:

Ubiquitin-specific protease

UPP:

Ubiquitin proteosomal pathway

DUBs:

Deubiquitinases

UB:

Ubiquitination

UBD:

Ubiquitin-binding domain

ZnF-UBP domain:

Zinc finger ubiquitin-specific protease domain

UIM:

Ubiquitin-interacting motif

UBA domain:

Ubiquitin-associated domain

UCHs:

Ubiquitin C-terminal hydrolases

OTUs:

Ovarian tumor proteases

MJD:

Machado–Joseph domain protease

FDA:

Food and drug administration

PI:

Proteasome inhibitor

MM:

Multiple myeloma

NSCLC:

Non-small cell lung cancer

Bcl-xL:

B-cell lymphoma-extra large

Bcl-2:

B-cell lymphoma 2

CDDP:

Cis-diaminedichloroplatin (II)

USP:

Ubiquitin-specific peptidase

UAF1:

WD repeat-containing protein 48

LCLs:

Lymphoblastoid cell lines

PTEN:

Phosphatase and tensin homolog

PARP:

Poly ADP ribose polymerase

MDM2:

Murine double minute oncogene

ER:

Estrogen receptor

EGFR:

Epidermal growth factor receptor

RTK:

Receptor tyrosine kinase

BAG3:

BAG family molecular chaperone regulator 3

Mcl-1:

Myeloid leukemia cell differentiation protein

TAM:

Tamoxifen

ERα:

Estrogen receptor α

FLT3-ITD:

FMS-like tyrosine kinase 3 internal tandem duplication

USP9x:

Ubiquitin-specific peptidase 9x

siRNA:

Small interfering RNA

TKD:

Tyrosine kinase domain

CAM-DR:

Cell adhesion-mediated drug resistance

WM:

Waldenstrom macroglobulinemia

BCR:

B-cell receptor

MYD88:

Myeloid differentiation primary response 88

PBMC:

Peripheral blood mononuclear cell

MDR:

Multidrug resistance

HCC:

Hepatocellular carcinoma

CSCs:

Cancer stem cells

SIRT1:

Silent mating type information regulation 2 homolog 1

MRP1:

Multidrug resistance-associated protein 1

NAFLD:

Non-alcoholic fatty liver disease

TAK1:

Transforming growth factor beta-activated kinase 1

TLS:

Translesion synthesis repair pathway

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Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (2017M3A9C6061361, 2018M3A9H3022412, 2017R1A2B2008727 and 2017M3A9B3061830).

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  1. Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, 04763, South Korea

    Parthasaradhireddy Tanguturi, Kye-Seong Kim & Suresh Ramakrishna

  2. College of Medicine, Hanyang University, Seoul, 04763, South Korea

    Kye-Seong Kim & Suresh Ramakrishna

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  1. Parthasaradhireddy Tanguturi
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Tanguturi, P., Kim, KS. & Ramakrishna, S. The role of deubiquitinating enzymes in cancer drug resistance. Cancer Chemother Pharmacol 85, 627–639 (2020). https://doi.org/10.1007/s00280-020-04046-8

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