Involvement of the ubiquitin-proteasome system in the regulation of the tumor microenvironment and progression

Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23(1):74-88.

Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309-322.

Xiao Y, Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol Ther. 2021;221:107753.

Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer. 2016;138(5):1058-1066.

Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metabol. 2016;23(1):27-47.

Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423-1437.

Shi R, Tang YQ, Miao H. Metabolism in tumor microenvironment: implications for cancer immunotherapy. MedComm. 2020;1(1):47-68.

Arner EN, Rathmell JC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell. 2023;41(3):421-433.

de Visser KE, Joyce JA. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41(3):374-403.

Huang TT, D'Andrea AD. Regulation of DNA repair by ubiquitylation. Nat Rev Mol Cell Biol. 2006;7(5):323-334.

Conaway RC, Brower CS, Conaway JW. Emerging roles of ubiquitin in transcription regulation. Science. 2002;296(5571):1254-1258.

Hicke L. Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol. 2001;2(3):195-201.

Komander D, Rape M. The ubiquitin code. Annu Rev Biochem. 2012;81:203-229.

Akutsu M, Dikic I, Bremm A. Ubiquitin chain diversity at a glance. J Cell Sci. 2016;129(5):875-880.

Yau R, Rape M. The increasing complexity of the ubiquitin code. Nat Cell Biol. 2016;18:579-586.

Kulathu Y, Komander D. Atypical ubiquitylation - the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol. 2012;13(8):508-523.

Wu X, Karin M. Emerging roles of Lys63-linked polyubiquitylation in immune responses. Immunol Rev. 2015;266(1):161-174.

Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem. 2001;70:503-533.

Morreale FE, Walden H. Types of ubiquitin ligases. Cell. 2016;165(1):248-248.e1.

Toma-Fukai S, Shimizu T. Structural diversity of ubiquitin E3 ligase. Molecules. 2021;26(21):6682.

Komander D, Clague MJ, Urbé S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009;10:550-563.

Lange SM, Armstrong LA, Kulathu Y. Deubiquitinases: from mechanisms to their inhibition by small molecules. Mol Cell. 2022;82(1):15-29.

Zhang J, Wan L, Dai X, Sun Y, Wei W. Functional characterization of anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin ligases in tumorigenesis. Biochim Biophys Acta. 2014;1845(2):277-293.

Zhou W, Wei W, Sun Y. Genetically engineered mouse models for functional studies of SKP₁-CUL1-F-box-protein (SCF) E3 ubiquitin ligases. Cell Res. 2013;23(5):599-619.

Liu J, Peng Y, Zhang J, Long J, Liu J, Wei W. Targeting SCF E3 ligases for cancer therapies. Adv Exp Med Biol. 2020;1217:123-146.

Li F, Mladenov E, Mortoga S, Iliakis G. SCF^SKP2 regulates APC/C^CDH1-mediated degradation of CTIP to adjust DNA-end resection in G₂-phase. Cell Death Dis. 2020;11(7):548.

Dang F, Nie L, Wei W. Ubiquitin signaling in cell cycle control and tumorigenesis. Cell Death Differ. 2021;28(2):427-438.

Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer. 2006;6(5):369-381.

Cao YF, Xie L, Tong BB, et al. Targeting USP10 induces degradation of oncogenic ANLN in esophageal squamous cell carcinoma. Cell Death Differ. 2023;30(2):527-543.

Bálint É, Vousden KH. Activation and activities of the p53 tumour suppressor protein. Br J Cancer. 2001;85(12):1813-1823.

Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene. 2005;24(17):2899-2908.

Hainaut P, Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv Cancer Res. 2000;77:81-137.

Corvi R, Savelyeva L, Breit S, et al. Non-syntenic amplification of MDM2 and MYCN in human neuroblastoma. Oncogene. 1995;10(6):1081-1086.

Pellegrino M, Mancini F, Lucà R, et al. Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy. Cancer Res. 2015;75(21):4560-4572.

Sdek P, Ying H, Chang DLF, et al. MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Mol Cell. 2005;20(5):699-708.

Wang C, Ivanov A, Chen L, et al. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J. 2005;24(18):3279-3290.

Su WJ, Fang JS, Cheng F, Liu C, Zhou F, Zhang J. RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development. Proc Natl Acad Sci U S A. 2013;110(5):1720-1725.

Nag A, Bagchi S, Raychaudhuri P. Cul4A physically associates with MDM2 and participates in the proteolysis of p53. Cancer Res. 2004;64(22):8152-8155.

Guo Y, Li Q, Zhao G, et al. Loss of TRIM31 promotes breast cancer progression through regulating K48- and K63-linked ubiquitination of p53. Cell Death Dis. 2021;12(10):945.

Allton K, Jain AK, Herz HM, et al. Trim24 targets endogenous p53 for degradation. Proc Natl Acad Sci USA. 2009;106(28):11612-11616.

Zhang X, Li CF, Zhang L, et al. TRAF6 restricts p53 mitochondrial translocation, apoptosis, and tumor suppression. Mol Cell. 2016;64(4):803-814.

Wang L, Wang L, Zhang S, et al. Downregulation of ubiquitin E3 ligase TNF receptor-associated factor 7 leads to stabilization of p53 in breast cancer. Oncol Rep. 2013;29(1):283-287.

Esser C, Scheffner M, Höhfeld J. The chaperone-associated ubiquitin ligase CHIP is able to target p53 for proteasomal degradation. J Biol Chem. 2005;280(29):27443-27448.

Peuget S, Selivanova G. MDM2-PROTAC versus MDM2 inhibitors: beyond p53 reactivation. Cancer Discov. 2023;13(5):1043-1045.

Zhu X, Xue J, Jiang X, et al. TRIM21 suppresses CHK₁ activation by preferentially targeting CLASPIN for K63-linked ubiquitination. Nucleic Acids Res. 2022;50(3):1517-1530.

Wang L, Hu T, Shen Z, et al. Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC. Cell Death Dis. 2022;13(11):951.

Granieri L, Marocchi F, Melixetian M, et al. Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors. Cell Rep. 2022;40(12):111396.

Hatzivassiliou G, Zhao F, Bauer DE, et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005;8(4):311-321.

Battaglioni S, Benjamin D, Wälchli M, Maier T, Hall MN. mTOR substrate phosphorylation in growth control. Cell. 2022;185(11):1814-1836.

He YM, Zhou XM, Jiang SY, et al. TRIM25 activates AKT/mTOR by inhibiting PTEN via K63-linked polyubiquitination in non-small cell lung cancer. Acta Pharmacol Sin. 2022;43(3):681-691.

Fang L, Ford-Roshon D, Russo M, et al. RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition. Nat Commun. 2022;13(1):3181.

Liu M, Gao S, Xu X, Zhang L, Xu B, Lu D. USP18 contributes to the proliferation and migration of ovarian cancer cells by regulating the AKT/mTOR signaling pathway. Acta Biochim Pol. 2022;69(2):417-422.

Wang D, Xu C, Yang W, et al. E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression. Mol Cell. 2022;82(4):770-784.e9.

Liu W, Zhao Y, Wang G, et al. TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling. Redox Biol. 2022;53:102344.

Cheng X, Zhang B, Guo F, Wu H, Jin X. Deubiquitination of FBP₁ by USP7 blocks FBP₁-DNMT1 interaction and decreases the sensitivity of pancreatic cancer cells to PARP inhibitors. Mol Oncol. 2022;16(7):1591-1607.

Cowman SJ, Koh MY. Revisiting the HIF switch in the tumor and its immune microenvironment. Trends Cancer. 2022;8(1):28-42.

McGettrick AF, O'Neill LAJ. The role of HIF in immunity and inflammation. Cell Metabol. 2020;32(4):524-536.

Robinson CM, Ohh M. The multifaceted von Hippel–Lindau tumour suppressor protein. FEBS Lett. 2014;588(16):2704-2711.

Zhang C, Peng Z, Zhu M, et al. USP9X destabilizes pVHL and promotes cell proliferation. Oncotarget. 2016;7(37):60519-60534.

Troilo A, Alexander I, Muehl S, Jaramillo D, Knobeloch KP, Krek W. HIF1α deubiquitination by USP8 is essential for ciliogenesis in normoxia. EMBO Rep. 2014;15(1):77-85.

Li Z, Wang D, Messing EM, Wu G. VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1α. EMBO Rep. 2005;6(4):373-378.

Goto Y, Zeng L, Yeom CJ, et al. UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α. Nat Commun. 2015;6:6153.

Schipani E. Hypoxia and HIF-1 alpha in chondrogenesis. Semin Cell Dev Biol. 2005;16(4–5):539-546.

Nelson JK, Thin MZ, Evan T, et al. USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer. Nat Commun. 2022;13(1):2070.

Ravi R, Mookerjee B, Bhujwalla ZM, et al. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev. 2000;14(1):34-44.

Joshi S, Singh AR, Durden DL. MDM2 regulates hypoxic hypoxia-inducible factor 1α stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner. J Biol Chem. 2014;289(33):22785-22797.

Koh MY, Lemos Jr R, Liu X, Powis G. The hypoxia-associated factor switches cells from HIF-1α- to HIF-2α-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res. 2011;71(11):4015-4027.

Zhang A, Huang Z, Tao W, et al. USP33 deubiquitinates and stabilizes HIF-2alpha to promote hypoxia response in glioma stem cells. EMBO J. 2022;41(7):e109187.

Ouyang G, Fu W, Guo J, et al. Hypoxia-induced UBE2K promotes the malignant progression of HCC. Pathol Res Pract. 2023;245:154422.

Zhou P, Peng X, Tang S, et al. E3 ligase MAEA-mediated ubiquitination and degradation of PHD3 promotes glioblastoma progression. Oncogene. 2023;42(16):1308-1320.

Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010;28:445-489.

Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol. 2009;27:591-619.

Yin X, Chen S, Eisenbarth SC. Dendritic cell regulation of T helper cells. Annu Rev Immunol. 2021;39:759-790.

Ghiringhelli F, Ménard C, Martin F, Zitvogel L. The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol Rev. 2006;214:229-238.

Sharma P, Goswami S, Raychaudhuri D, et al. Immune checkpoint therapy —current perspectives and future directions. Cell. 2023;186(8):1652-1669.

Hu X, Wang J, Chu M, Liu Y, Wang ZW, Zhu X. Emerging role of ubiquitination in the regulation of PD-1/PD-L1 in cancer immunotherapy. Mol Ther. 2021;29(3):908-919.

Meng X, Liu X, Guo X, et al. FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells. Nature. 2018;564(7734):130-135.

Zhou XA, Zhou J, Zhao L, et al. KLHL22 maintains PD-1 homeostasis and prevents excessive T cell suppression. Proc Natl Acad Sci U S A. 2020;117(45):28239-28250.

Yang Z, Xu G, Wang B, et al. USP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade. Nat Commun. 2021;12:4852.

Wu Z, Cao Z, Yao H, et al. Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2. Cell Rep. 2023;42(7):112693.

Lyle C, Richards S, Yasuda K, et al. c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth. Sci Rep. 2019;9(1):20257.

Sun K, Zhang X, Lao M, et al. Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy. Mol Ther. 2023;31(10):2929-2947.

Jiang C, He L, Xiao S, Wu W, Zhao Q, Liu F. E3 ubiquitin ligase RNF125 suppresses immune escape in head and neck squamous cell carcinoma by regulating PD-L1 expression. Mol Biotechnol. 2023;65(6):891-903.

Dong LF, Chen FF, Fan YF, Zhang K, Chen HH. Circ-0000512 inhibits PD-L1 ubiquitination through sponging miR-622/CMTM6 axis to promote triple-negative breast cancer and immune escape. J Immunother Cancer. 2023;11(6):e005461.

Ma X, Jia S, Wang G, et al. TRIM28 promotes the escape of gastric cancer cells from immune surveillance by increasing PD-L1 abundance. Signal Transduct Targeted Ther. 2023;8:246.

Lim SO, Li CW, Xia W, et al. Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell. 2016;30(6):925-939.

Wang Y, Sun Q, Mu N, et al. The deubiquitinase USP22 regulates PD-L1 degradation in human cancer cells. Cell Commun Signal. 2020;18(1):112.

Zhang X, Cheng L, Gao C, et al. Androgen signaling contributes to sex differences in cancer by inhibiting NF-κB activation in T cells and suppressing antitumor immunity. Cancer Res. 2023;83(6):906-921.

Yao Y, Pan L, Wei Y, et al. TRIM21 promotes inflammation by ubiquitylating NF-κB in T cells of oral lichen planus. J Oral Pathol Med. 2023;52(5):448-455.

Singh A, Choudhury SD, Singh P, Kaushal S, Sharma A. Disruption in networking of KCMF1 linked ubiquitin ligase impairs autophagy in CD8⁺ memory T cells of patients with renal cell carcinoma. Cancer Lett. 2023;564:216194.

Li J, Yuan S, Norgard RJ, et al. Tumor cell–intrinsic USP22 suppresses antitumor immunity in pancreatic cancer. Cancer Immunol Res. 2020;8(3):282-291.

Lee JY, An EK, Hwang J, Jin JO, Lee PCW. Ubiquitin activating enzyme UBA6 regulates Th1 and Tc1 cell differentiation. Cells. 2021;11(1):105.

Wang X, Guan F, Miller H, et al. The role of dendritic cells in COVID-19 infection. Emerg Microb Infect. 2023;12(1):2195019.

Dudziak D, Kamphorst AO, Heidkamp GF, et al. Differential antigen processing by dendritic cell subsets in vivo. Science. 2007;315(5808):107-111.

Zhu B, Zhu L, Xia L, Xiong Y, Yin Q, Rui K. Roles of ubiquitination and deubiquitination in regulating dendritic cell maturation and function. Front Immunol. 2020;11:586613.

Oh J, Wu N, Baravalle G, et al. MARCH1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells. J Exp Med. 2013;210(6):1069-1077.

De Angelis Rigotti F, De Gassart A, Pforr C, et al. MARCH9-mediated ubiquitination regulates MHC I export from the TGN. Immunol Cell Biol. 2017;95(9):753-764.

Yang H, Qiu Q, Gao B, Kong S, Lin Z, Fang D. Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation. J Exp Med. 2014;211(12):2467-2479.

Reinicke AT, Raczkowski F, Mühlig M, et al. Deubiquitinating enzyme UCH-L1 promotes dendritic cell antigen cross-presentation by favoring recycling of MHC class I molecules. J Immunol. 2019;203(7):1730-1742.

Kool M, Van Loo G, Waelput W, et al. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity. 2011;35(1):82-96.

Liu J, Han C, Xie B, et al. Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO. Nat Immunol. 2014;15(7):612-622.

Hammer GE, Turer EE, Taylor KE, et al. Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol. 2011;12(12):1184-1193.

Liao L, Song M, Li X, et al. E3 ubiquitin ligase UBR5 drives the growth and metastasis of triple-negative breast cancer. Cancer Res. 2017;77(8):2090-2101.

Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445-455.

Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. Pillars article: M-1/M-2 macrophages and the Th1/Th2 paradigm. J. immunol. 2000.164:6166–6173. J Immunol. 2017;199(7):2194-2201.

Sica A, Mantovani A. Macrophage plasticity and polarization: In vivo veritas. J Clin Invest. 2012;122(3):787-795.

Xu L, Wang L, Yang R, Li T, Zhu X. Lung adenocarcinoma cell-derived exosomes promote M2 macrophage polarization through transmission of miR-3153 to activate the JNK signaling pathway. Hum Mol Genet. 2023;32(13):2162-2176.

Zhong J, Wang H, Chen W, et al. Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways. Cell Death Dis. 2017;8(5):e2763.

Kim D, Koh J, Ko JS, Kim HY, Lee H, Chung DH. Ubiquitin E3 ligase pellino-1 inhibits IL-10-mediated M2c polarization of macrophages, thereby suppressing tumor growth. Immune Netw. 2019;19(5):e32.

Lin X, Zhang H, Boyce BF, Xing L. Ubiquitination of interleukin-1α is associated with increased pro-inflammatory polarization of murine macrophages deficient in the E3 ligase ITCH. J Biol Chem. 2020;295(33):11764-11775.

Zhong L, Zhang Y, Li M, et al. E3 ligase FBXW7 restricts M2-like tumor-associated macrophage polarization by targeting c-Myc. Aging. 2020;12(23):24394-24423.

Yu T, Gan S, Zhu Q, et al. Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24. Nat Commun. 2019;10(1):4353.

Liu X, Fang Y, Lv X, et al. Deubiquitinase OTUD6A in macrophages promotes intestinal inflammation and colitis via deubiquitination of NLRP3. Cell Death Differ. 2023;30(6):1457-1471.

Zhao X, Huang XH, Dong XH, et al. Deubiquitinase Mysm1 regulates macrophage survival and polarization. Mol Biol Rep. 2018;45(6):2393-2401.

Zhang Y, Fan Y, Jing X, et al. OTUD5-mediated deubiquitination of YAP in macrophage promotes M2 phenotype polarization and favors triple-negative breast cancer progression. Cancer Lett. 2021;504:104-115.

Piccione EC, Juarez S, Tseng S, et al. SIRPα-antibody fusion proteins selectively bind and eliminate dual antigen-expressing tumor cells. Clin Cancer Res. 2016;22(20):5109-5119.

Deuse T, Hu X, Agbor-Enoh S, et al. The SIRPα-CD47 immune checkpoint in NK cells. J Exp Med. 2021;218(3):e20200839.

Hu T, Liu H, Liang Z, et al. Tumor-intrinsic CD47 signal regulates glycolysis and promotes colorectal cancer cell growth and metastasis. Theranostics. 2020;10(9):4056-4072.

Zhou Z, Song X, Wavelet CM, Wan Y. Cullin 4-DCAF proteins in tumorigenesis. Adv Exp Med Biol. 2020;1217:241-259.

Logtenberg MEW, Scheeren FA, Schumacher TN. The CD47-SIRPα immune checkpoint. Immunity. 2020;52(5):742-752.

Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19(2):108-119.

Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res. 2015;128:95-139.

Hegde S, Leader AM, Merad M. MDSC: markers, development, states, and unaddressed complexity. Immunity. 2021;54(5):875-884.

Dysthe M, Parihar R. Myeloid-derived suppressor cells in the tumor microenvironment. Adv Exp Med Biol. 2020;1224:117-140.

Zhan X, He Q, Sheng J, et al. USP12 positively regulates M-MDSC function to inhibit antitumour immunity through deubiquitinating and stabilizing p65. Immunology. 2022;167(4):544-557.

Song G, Zhang Y, Tian J, et al. TRAF6 regulates the immunosuppressive effects of myeloid-derived suppressor cells in tumor-bearing host. Front Immunol. 2021;12:649020.

Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582-598.

Lambies G, Miceli M, Martínez-Guillamon C, et al. TGFβ-activated USP27X deubiquitinase regulates cell migration and chemoresistance via stabilization of Snail1. Cancer Res. 2019;79(1):33-46.

Kim E, Kim W, Lee S, et al. TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts. Sci Rep. 2017;7(1):8923.

Lee JH, Jung SM, Yang KM, et al. A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1. Nat Cell Biol. 2017;19(10):1260-1273.

Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212-20217.

Chen IX, Chauhan VP, Posada J, et al. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc Natl Acad Sci U S A. 2019;116(10):4558-4566.

Shen YW, Zhou YD, Chen HZ, Luan X, Zhang WD. Targeting CTGF in cancer: an emerging therapeutic opportunity. Trends Cancer. 2021;7(6):511-524.

Loewenstein S, Lubezky N, Nizri E, et al. Adipose-induced retroperitoneal soft tissue sarcoma tumorigenesis: a potential crosstalk between sarcoma and fat cells. Mol Cancer Res. 2016;14(12):1254-1265.

Liu X, Lu Y, Chen Z, et al. The ubiquitin-specific peptidase USP18 promotes lipolysis, fatty acid oxidation, and lung cancer growth. Mol Cancer Res. 2021;19(4):667-677.

Gordon MK, Hahn RA. Collagens. Cell Tissue Res. 2010;339(1):247-257.

De Martino D, Bravo-Cordero JJ. Collagens in cancer: structural regulators and guardians of cancer progression. Cancer Res. 2023;83(9):1386-1392.

Eom YS, Ko BS, Shah FH, Kim SJ. E3 ubiquitin ligase constitutive photomorphogenic 1 regulates differentiation and inflammation via MAPK signaling pathway in rabbit articular chondrocytes. DNA Cell Biol. 2023;42(5):239-247.

Wu X, Wang H, Zhu D, et al. USP3 promotes gastric cancer progression and metastasis by deubiquitination-dependent COL9A3/COL6A5 stabilisation. Cell Death Dis. 2021;13:10.

Suzuki T, Dai Y, Ono M, et al. Pivotal role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in uterine leiomyoma. Biomolecules. 2023;13(2):193.

Overall CM, Kleifeld O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6(3):227-239.

Vandenbroucke RE, Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov. 2014;13:904-927.

Liu J, Chen T, Li S, Liu W, Wang P, Shang G. Targeting matrix metalloproteinases by E3 ubiquitin ligases as a way to regulate the tumor microenvironment for cancer therapy. Semin Cancer Biol. 2022;86(Pt 2):259-268.

Oldak L, Chludzinska-Kasperuk S, Milewska P, Grubczak K, Reszec J, Gorodkiewicz E. MMP-1, UCH-L1, and 20S proteasome as potential biomarkers supporting the diagnosis of brain glioma. Biomolecules. 2022;12(10):1477.

Xu J, Zhou W, Yang F, et al. The β-TrCP-FBXW2-SKP₂ axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor. Nat Commun. 2017;8:14002.

Ren C, Han X, Lu C, et al. Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance. Cell Death Differ. 2022;29(2):381-392.

Hung WC, Tseng WL, Shiea J, Chang HC. Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett. 2010;288(2):156-161.

Chen W, Ni D, Zhang H, et al. Over-expression of USP15/MMP3 predict poor prognosis and promote growth, migration in non-small cell lung cancer cells. Cancer Genet. 2023;272–273:9-15.

Venkatesan T, Alaseem A, Chinnaiyan A, et al. MDM2 overexpression modulates the angiogenesis-related gene expression profile of prostate cancer cells. Cells. 2018;7(5):41.

Bradbury R, Jiang WG, Cui YX. MDM2 and PSMA play inhibitory roles in metastatic breast cancer cells through regulation of matrix metalloproteinases. Anticancer Res. 2016;36(3):1143-1151.

Li H, Qu L, Zhou R, et al. TRIM13 inhibits cell migration and invasion in clear-cell renal cell carcinoma. Nutr Cancer. 2020;72(7):1115-1124.

Tan X, He X, Fan Z. Upregulation of HRD1 promotes cell migration and invasion in colon cancer. Mol Cell Biochem. 2019;454(1):1-9.

Zhang B, Yang C, Wang R, et al. OTUD7B suppresses Smac mimetic-induced lung cancer cell invasion and migration via deubiquitinating TRAF₃. J Exp Clin Cancer Res. 2020;39(1):244.

Bogyo M, McMaster JS, Gaczynska M, Tortorella D, Goldberg AL, Ploegh H. Covalent modification of the active site threonine of proteasomal β subunits and the Escherichia coli homolog HslV by a new class of inhibitors. Proc Natl Acad Sci U S A. 1997;94(13):6629-6634.

Ambrosio FA, Costa G, Gallo Cantafio ME, et al. Natural agents as novel potential source of proteasome inhibitors with anti-tumor activity: focus on multiple myeloma. Molecules. 2023;28(3):1438.

Robak T, Huang H, Jin J, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015;372(10):944-953.

Muranushi H, Kanda J, Kobayashi M, et al. Bortezomib-cyclophosphamide-dexamethasone induction/consolidation and bortezomib maintenance for transplant-eligible newly diagnosed multiple myeloma: phase 2 multicenter trial. Hematology. 2022;27(1):239-248.

Velasco R, Alberti P, Bruna J, Psimaras D, Argyriou AA. Bortezomib and other proteosome inhibitors-induced peripheral neurotoxicity: from pathogenesis to treatment. J Peripher Nerv Syst. 2019;24(Suppl 2):S52-S62.

Yamamoto S, Egashira N. Pathological mechanisms of bortezomib-induced peripheral neuropathy. Int J Mol Sci. 2021;22(2):888.

Li YL. Analysis of bortezomib treatment efficacy and adverse reactions for patients with follicular lymphoma. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2015;23(1):119-122.

Aghajanian C, Soignet S, Dizon DS, et al. A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res. 2002;8(8):2505-2511.

Franke NE, Niewerth D, Assaraf YG, et al. Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia. 2012;26(4):757-768.

Slade M, Martin TG, Nathwani N, et al. Ixazomib, lenalidomide and dexamethasone consolidation with randomized ixazomib or lenalidomide maintenance after autologous transplant in newly diagnosed multiple myeloma. Leukemia. 2022;36(12):2917-2921.

Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992;69(7):1237-1245.

Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303(5659):844-848.

Wu D, Li Y, Li C, et al. MDM2 antagonist nutlin-3 stimulates global DNA hydroxymethylation by enhancing p53-TET1 signaling axis. ACS Chem Biol. 2023;18(10):2240-2248.

Konopleva M, Martinelli G, Daver N, et al. MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020;34(11):2858-2874.

LoRusso P, Yamamoto N, Patel MR, et al. The MDM2-p53 antagonist brigimadlin (BI 907828) in patients with advanced or metastatic solid tumors: results of a phase ia, first-in-human, dose-escalation study. Cancer Discov. 2023;13(8):1802-1813.

Zhu H, Gao H, Ji Y, et al. Targeting p53-MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials. J Hematol Oncol. 2022;15(1):91.

Sakamoto KM, Kim KB, Verma R, et al. Development of protacs to target cancer-promoting proteins for ubiquitination and degradation. Mol Cell Proteomics. 2003;2(12):1350-1358.

Nieto-Jiménez C, Morafraile EC, Alonso-Moreno C, Ocaña A. Clinical considerations for the design of PROTACs in cancer. Mol Cancer. 2022;21(1):67.

Adams CM, Mitra R, Xiao Y, et al. Targeted MDM2 degradation reveals a new vulnerability for p53-inactivated triple-negative breast cancer. Cancer Discov. 2023;13(5):1210-1229.

Lai AC, Toure M, Hellerschmied D, et al. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew Chem Int Ed. 2016;55(2):807-810.

Jiang ZY, Hong J, Zhang JH, et al. Treatment with b-AP15 to inhibit UCHL5 and USP14 deubiquitinating activity and enhance p27 and cyclin E1 for tumors with p53 deficiency. Technol Cancer Res Treat. 2022;21:15330338221119745.

Paulus A, Akhtar S, Caulfield TR, et al. Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells. Blood Cancer J. 2016;6(11):e492.

Chan WC, Liu X, Magin RS, et al. Accelerating inhibitor discovery for deubiquitinating enzymes. Nat Commun. 2023;14(1):686.