Abstract

摘要： 乳腺癌的临床治疗中,肿瘤复发和治疗耐药仍然构成主要挑战。泛素特异性蛋白酶8（USP8）是一种重要的去泛素化酶,近年来逐渐成为该领域的研究焦点。多项研究表明,USP8在乳腺癌组织中经常呈现异常表达,其主要通过阻遏雌激素受体α（ERα）和Notch信号通路等关键致癌蛋白的泛素化降解,促进肿瘤细胞的增殖、侵袭和转移,并参与内分泌治疗耐药的发生。此外,USP8还可调控肿瘤微环境,导致免疫抑制状态的形成,进而削弱免疫治疗的疗效。现有实验证据显示,针对USP8的小分子抑制剂具有显著的抗肿瘤活性。因此,进一步阐明USP8在乳腺癌中的分子机制,将有助于发现新型治疗靶点,尤其为克服耐药性的乳腺癌患者提供潜在的干预策略。

关键词: 乳腺癌, USP8, 作用机制, 研究进展

CLC Number:

R737.9

张瑞元, 刘赛璇, 赵杨, 申兴斌. USP8在乳腺癌中作用机制的研究进展[J]. 承德医学院学报, 2026, 43(4): 324-329.

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References

[1] Li T, Zhang H, Lian M, et al.Global status and attributable risk factors of breast, cervical, ovarian, and uterine cancers from 1990 to 2021[J]. J Hematol Oncol, 2025, 18(1): 5.
[2] Bray F, Laversanne M, Sung H, et al.Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[3] Liu S, Zhang X, Wang W, et al.Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer[J]. Mol Cancer, 2024, 23(1): 261.
[4] Gao H, Yin J, Ji C, et al.Targeting ubiquitin specific proteases (USPs) in cancer immunotherapy: from basic research to preclinical application[J]. J Exp Clin Cancer Res, 2023, 42(1): 225.
[5] Islam M T, Chen F, Chen H.The oncogenic role of ubiquitin specific peptidase (USP8) and its signaling pathways targeting for cancer therapeutics[J]. Arch Biochem Biophys, 2021, 701: 108811.
[6] Fang Y Z, Jiang L, He Q, et al.Deubiquitination complex platform: a plausible mechanism for regulating the substrate specificity of deubiquitinating enzymes[J]. Acta Pharm Sin B, 2023, 13(7): 2955-2962.
[7] Dufner A, Knobeloch K P.Ubiquitin-specific protease 8 (USP8/UBPy): a prototypic multidomain deubiquitinating enzyme with pleiotropic functions[J]. Biochem Soc Trans, 2019, 47(6): 1867-1879.
[8] Caba C, Black M, Liu Y, et al.Autoinhibition of ubiquitin-specific protease 8: insights into domain interactions and mechanisms of regulation[J]. J Biol Chem, 2024, 300(10): 107727.
[9] Komada M.Controlling receptor downregulation by ubiquitination and deubiquitination[J]. Curr Drug Discov Technol, 2008, 5(1): 78-84.
[10] Row P E, Prior I A, McCullough J, et al. The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation[J]. J Biol Chem, 2006, 281(18): 12618-12624.
[11] Row P E, Liu H, Hayes S, et al.The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required for efficient epidermal growth factor receptor degradation[J]. J Biol Chem, 2007, 282(42): 30929-30937.
[12] Pohl C, Jentsch S.Final stages of cytokinesis and midbody ring formation are controlled by BRUCE[J]. Cell, 2008, 132(5): 832-845.
[13] Yeates E F A, Tesco G. The endosome-associated deubiquitinating enzyme USP8 regulates BACE1 enzyme ubiquitination and degradation[J]. J Biol Chem, 2016, 291(30): 15753-15766.
[14] Mohammed A A.The clinical behavior of different molecular subtypes of breast cancer[J]. Cancer Treat Res Commun, 2021, 29: 100469.
[15] Xiong X, Zheng L W, Ding Y, et al.Breast cancer: pathogenesis and treatments[J]. Signal Transduct Target Ther, 2025, 10(1): 49.
[16] Zheng L, Yang Q, Li C, et al.Ubiquitin-Specific Peptidase 8 Modulates Cell Proliferation and Induces Cell Cycle Arrest and Apoptosis in Breast Cancer by Stabilizing Estrogen Receptor Alpha[J]. J Oncol, 2023, 2023(1): 8483325.
[17] Xie F, Zhou X, Li H, et al.USP8 promotes cancer progression and extracellular vesicle-mediated CD8+ T cell exhaustion by deubiquitinating the TGF-β receptor TβRII[J]. EMBO J, 2022, 41(16): e108791.
[18] Qiu H, Kong J, Cheng Y, et al.The expression of ubiquitin-specific peptidase 8 and its prognostic role in patients with breast cancer[J]. J Cell Biochem, 2018, 119(12): 10051-10058.
[19] Baker A, Wyatt D, Bocchetta M, et al.Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival[J]. Oncogene, 2018, 37(33): 4489-4504.
[20] Shin S, Kim K, Kim H R, et al.Deubiquitylation and stabilization of Notch1 intracellular domain by ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer[J]. Cell Death Differ, 2020, 27(4): 1341-1354.
[21] Huang S, Hölzel M, Knijnenburg T, et al.MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling[J]. Cell, 2012, 151(5): 937-950.
[22] Khan O, Giles J R, McDonald S, et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion[J]. Nature, 2019, 571(7764): 211-218.
[23] Li Y, Jin K, van Pelt G W, et al. c-Myb enhances breast cancer invasion and metastasis through the Wnt/β-catenin/Axin2 pathway[J]. Cancer Res, 2016, 76(11): 3364-3375.
[24] Liu S, González-Prieto R, Zhang M, et al.Deubiquitinase activity profiling identifies UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis[J]. Clin Cancer Res, 2020, 26(6): 1460-1473.
[25] Xiong W, Gao X, Zhang T, et al.USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy[J]. Nat Commun, 2022, 13(1): 1700.
[26] Hegde PS, Chen DS.Top 10 challenges in cancer immunotherapy[J]. Immunity, 2020, 52(1): 17-35.
[27] Galluzzi L, Chan T A, Kroemer G, et al. The hallmarks of successful anticancer immunotherapy[J]. Sci Transl Med, 2018, 10(459): eaat7807.
[28] Zhao Y, Peng D, Liu Y, et al.Usp8 promotes tumor cell migration through activating the JNK pathway[J]. Cell Death Dis, 2022, 13(3): 286.
[29] Fan Y, Yu Y, Shi Y, et al.Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor α-and interleukin-1β-induced IKK/NF-κB and JNK/AP-1 activation[J]. J Biol Chem, 2010, 285(8): 5347-5360.
[30] Fan Y, Shi Y, Liu S, et al.Lys48-linked TAK1 polyubiquitination at lysine-72 downregulates TNFα-induced NF-κB activation via mediating TAK1 degradation[J]. Cell Signalling, 2012, 24(7): 1381-1389.
[31] Xie X, Liang H, Jiangting W, et al.Cancer-testis antigen CEP55 serves as a prognostic biomarker and is correlated with immune infiltration and immunotherapy efficacy in pan-cancer[J]. Front Mol Biosci, 2023, 10: 1198557.
[32] Zhang J, Zhang X.Clinicopathological and prognostic role of CEP55 expression in cancer patients: A meta-analysis of 31 studies with 12,543 patients[J]. iLABMED, 2024, 2(4): 327-340.
[33] Chen S, Luo Y, Ruan S, et al.RNA binding protein ILF3 increases CEP55 mRNA stability to enhance malignant potential of breast cancer cells and suppress ferroptosis[J]. Hereditas, 2025, 162(1): 10.
[34] Wang L, Wang Y, Liu C, et al.The USP8/CEP55/CHMP6 Axis Orchestrates Triple-Negative Breast Cancer Progression by Regulating Ferroptosis and Macrophage M2 Polarization[J]. Clin Breast Cancer, 2025: S1526820925002307.
[35] Tian Y, Liu K, Liu R, et al.Discovery of potent small-molecule USP8 inhibitors for the treatment of breast cancer through regulating ERα expression[J]. J Med Chem, 2022, 65(13): 8914-8932.
[36] Hu B, Liu Y, Zhao Z, et al.Isoginkgetin as a novel USP8 inhibitor discovered by structure-based virtual screening exerts anticancer effects in ovarian cancer[J]. Biochem Biophys Res Commun, 2025, 791: 152924.
[37] Tian Y, Liu K, Wu D, et al.The discovery of potent USP2/USP8 dual-target inhibitors for the treatment of breast cancer via structure guided optimization of ML364[J]. Eur J Med Chem, 2024, 268: 116275.

USP8在乳腺癌中作用机制的研究进展

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