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The crosstalk between ubiquitination and endocrine therapy

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Abstract

Endocrine therapy (ET), also known as hormone therapy, refers to the treatment of tumors by regulating and changing the endocrine environment and hormone levels. Its related mechanism is mainly through reducing hormone levels and blocking the binding of hormones to corresponding receptors, thus blocking the signal transduction pathway to stimulate tumor growth. However, with the application of ET, some patients show resistance to ET, which is attributed to abnormal accumulation of hormone receptors (HRs) and the production of multiple mutants of HRs. The targeted degradation of abnormal accumulation protein mediated by ubiquitination is an important approach that regulates the protein level and function of intracellular proteins in eukaryotes. Here, we provide a brief description of the traditional and novel drugs available for ET in this review. Then, we introduce the link between ubiquitination and ET. In the end, we elaborate the clinical application of ET combined with ubiquitination-related molecules.

Key messages

• A brief description of the traditional and novel drugs available for endocrine therapy (ET).

• The link between ubiquitination and ET.

• The clinical application of ET combined with ubiquitination-related molecules.

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Abbreviations

ADT:

Androgen deprivation therapy

AI:

Aromatase inhibitor

AIL:

Ailanthone

AMBRA1:

Autophagy and beclin 1 regulator 1

AMFR:

Autocrine mobility factor receptor

AR:

Androgen receptor

AR-Vs:

AR splicing variants

ATA:

Acetyltanshinone IIA

BA:

Betulinic acid

BAG6:

BCL2-associated athanogene cochaperone 6

BC:

Breast cancer

BCNU:

1,3-BIS (2-chloroethyl)-1-nitrosourea

BETP:

Bromodomain extraterminal protein

CBL:

Casitas B-lineage lymphoma

CDK:

Cyclin-dependent kinase

CHIP:

Carboxyl terminus of Hsc70-interacting protein

CK:

Cytokeratin

COPS5:

COP9 complex-associated isopeptidase

CRC:

Colorectal carcinoma

CRPC:

Castration-resistant prostate cancer

CSN:

COP9 signalosome

CUEDC2:

CUE domain containing 2

Cx43:

Connexin 43

CYP17:

Cytochrome P450c17

DFS:

Disease-free survival

DUB:

De-ubiquitination enzyme

E1:

Ubiquitin-activating enzyme

E2:

Ubiquitin-conjugation enzyme

E3:

Ubiquitin ligase

EC:

Endometrial cancer

Efp:

Estrogen-responsive finger protein

EGCG:

Baicalein and epigallocatechin-3-gallate

ER:

Estrogen receptor

ET:

Endocrine therapy

FASN:

Fatty acid synthetase

FDA:

Food and Drug Administration

FKBPL:

FK506-binding protein like

FSH:

Follicle-stimulating hormone

GET4:

General transcription factor group E4

GnRHa:

Gonadotropin-releasing hormone agonist

GR:

Glucocorticoid receptor

HCC:

Hepatocellular carcinoma

HOIL-1:

Heme-oxidized IRP2 ubiquitin ligase-1

HR:

Hormone receptor

HSP70:

Heat shock protein 70

IRF8:

Interferon regulatory factor 8

KLF4:

Kruppel-like factor 4

KLF5:

Kruppel-like zinc finger transcription factor 5

LH:

Luteinizing hormone

LMB:

Leptomycin B

LNX1:

Ligand-of-Numb protein X1

L-THP:

L-Tetrahydropalmatine

NLS:

Nuclear localization sequence

OFS:

Ovarian function inhibitor

OS:

Overall survival

PCa:

Prostate cancer

PFKFB3 :

6-Phosphate fructose 2-kinase/fructose 2,6-bisphosphatase-3

PFS:

Progression-free survival

PP1:

Protein phosphatase-1

PR:

Progesterone receptor

PROTAC:

Proteolysis targeting chimera

PSA:

Prostate-specific antigen

RB:

Retinoblastoma tumor suppressor gene products

RCC:

Renal cell carcinoma

SAT:

Second-line antiandrogen therapy

SERD:

Selective estrogen receptor degrader

SERM:

Selective estrogen receptor modulator

Siah2:

Seven in Absentia Homolog 2

TC:

Thyroid cancer

TRIM:

Tripartite motif

TSA:

Trichostatin A

TSH:

Thyroid-stimulating hormone

TTF:

Time to tumor failure

TTP:

Time to tumor progression

Type I:

Estrogen-dependent EC

Type II:

Non-estrogen-dependent EC

UPS:

Ubiquitin-proteasome system

USP7:

Ubiquitin-specific protease 7

WWP1:

WW domain containing E3 ubiquitin protein ligase 1

β-TrCP:

β-Transducin repeat-containing proteins

11β-HSD2:

11β-Hydroxysteroid dehydrogenase-2

3βHSD1:

3β Hydroxy steroid dehydrogenase 1

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Funding

This research was funded by the 2022 General Program-Education Department of Zhejiang Province (Y202249882), the National Natural Science Foundation of China (32270821), the Natural Science Foundation of Ningbo (Grant No. 2021J065), the Fundamental Research Funds for the Provincial Universities of Zhejiang (Grant No. SJLZ2022004), and the K.C. Wong Magna Fund in the Ningbo University.

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  1. Yidong Ge and Ziqing Zhan contributed equally to this study.

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  1. The Department of Medical Oncology, The First Hospital of Ningbo University, Ningbo University, Ningbo, 315010, China

    Yidong Ge, Ziqing Zhan, Meng Ye & Xiaofeng Jin

  2. Department of Biochemistry and Molecular Biology, Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Medical School of Ningbo University, Ningbo University, Ningbo, Zhejiang, 315211, China

    Yidong Ge, Ziqing Zhan, Meng Ye & Xiaofeng Jin

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Yidong Ge and Ziqing Zhan drafted the manuscript. Xiaofeng Jin and Meng Ye made substantial contributions to the interpretation, drafting the study, and revising it critically for important intellectual content. All authors read and approved the final manuscript.

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Ge, Y., Zhan, Z., Ye, M. et al. The crosstalk between ubiquitination and endocrine therapy. J Mol Med 101, 461–486 (2023). https://doi.org/10.1007/s00109-023-02300-z

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