Role of USP10/METTL3/CXCR4 Axis in Immunotherapy of Castration-Resistant Prostate Cancer
Abstract
The aim of this study was to investigate the role of the ubiquitin specific peptidase 10 (USP10/methyltransferase like 3 (METTL3)/C-X-C chemokine receptor type 4 (CXCR4) axis in immunotherapy of castration-resistant prostate cancer (CRPC).
Knockdown experiments were conducted in CRPC cell lines to assess the effect of targeting CXCR4 on cell proliferation invasion and migration. Coculture experiments of CXCR4 knockdown CRPC cells with THP1-M0 were performed to evaluate their impact on macrophage polarization and migration ability. With CD8+ T cells was conducted to assess their effects on CD8+ T cell proliferation and apoptosis. CXCR4-overexpressing CRPC cells were treated with the JAK-2 specific inhibitor AG490 to assess the effect of CXCR4 through the JAK2/STAT3 pathway on CRPC. The mechanisms by which USP10 regulates CXCR4 expression through targeting METTL3 were explored through dataset analysis, bioinformatics prediction, and Western blot.
In CRPC tissues and cells, there was an observed increase in CXCR4 expression. Suppressing CXCR4 through knockdown methods resulted in the inhibition of CRPC cell growth, movement, and infiltration. Additionally, it led to a reduction in M2 polarization and the recruitment of Tohoku Hospital Pediatrics-1 (THP1) M0 macrophages, along with a mitigation of CD8+ T cell exhaustion. Dataset analysis, bioinformatics prediction, and Western blot validation indicated that CXCR4 activates the JAK2/STAT3 pathway to promote the expression of CCL2 and PD-L1, while USP10 promotes CXCR4 expression through METTL3.
Our study underscores the significance of the USP10/METTL3/CXCR4 axis in immunotherapy for CRPC and CXCR4 as a potential target for therapeutic intervention in CRPC treatment.
2. Bergengren O, Pekala KR, Matsoukas K, Fainberg J, Mungovan SF, Bratt O, et al. 2022 Update on Prostate Cancer Epidemiology and Risk Factors-A Systematic Review. Eur Urol. 2023;84(2):191-206.
3. Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022[J]. Journal of the National Cancer Center, 2024, 4(1): 47-53.
4. Yu EM, Aragon-Ching JB. Advances with androgen deprivation therapy for prostate cancer. Expert Opin Pharmaco. 2022;23(9):1015-33.
5. Le TK, Duong QH, Baylot V, Fargette C, Baboudjian M, Colleaux L, et al. Castration-Resistant Prostate Cancer: From Uncovered Resistance Mechanisms to Current Treatments. Cancers. 2023;15(20):5047.
6. Lanka SM, Zorko NA, Antonarakis ES, Barata PC. Metastatic Castration-Resistant Prostate Cancer, Immune Checkpoint Inhibitors, and Beyond. Curr Oncol. 2023;30(4):4246-56.
7. Wang K, Ruan H, Xu T, Liu L, Liu D, Yang H, Zhang X, Chen K. Recent advances on the progressive mechanism and therapy in castration-resistant prostate cancer. Onco Targets Ther. 2018:3167-78.
8. Hegde P S, Chen D S. Top 10 challenges in cancer immunotherapy. Immunity. 2020;52(1): 17-35.
9. Kallingal A, Olszewski M, Maciejewska N, Brankiewicz W, Baginski M. Cancer immune escape: the role of antigen presentation machinery. J Cancer Res Clin. 2023;149(10):8131-41.
10. Bansal D, Reimers MA, Knoche EM, Pachynski RK. Immunotherapy and Immunotherapy Combinations in Metastatic Castration-Resistant Prostate Cancer. Cancers. 2021;13(2):334.
11. Jin H, Zhu J, Xuan R, et al. A Crosstalk Between Castration-Resistant Prostate Cancer Cells, M2 Macrophages, and NK Cells: Role of the ATM-PI3K/AKT-PD-L1 Pathway. Immunol Invest. 2023;52(8):941-965.
12. Jin H, Zhu J, Xuan R, Zhou Y, Xue B, Yang D, et al. A Crosstalk Between Castration-Resistant Prostate Cancer Cells, M2 Macrophages, and NK Cells: Role of the ATM-PI3K/AKT-PD-L1 Pathway. Immunol Invest. 2023;52(8):941-65.
13. Xu L, Chen X, Shen M, Yang DR, Fang L, Weng G, et al. Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels. Mol Oncol. 2018;12(3):269-86.
14. Harper M M, Lin M, Cavnar M J. Interaction of immune checkpoint PD-1 and chemokine receptor 4 (CXCR4) promotes a malignant phenotype in pancreatic cancer cells. Plos one. 2022;17(7): e0270832.
15. Seo YD, Jiang X, Sullivan KM, Jalikis FG, Smythe KS, Abbasi A, et al. Mobilization of CD8(+) T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer. Clin Cancer Res. 2019;25(13):3934-45.
16. Liu P, Liu Y, Chen L, Fan Z, Luo Y, Cui Y. Anemoside A3 Inhibits Macrophage M2-Like Polarization to Prevent Triple-Negative Breast Cancer Metastasis. Molecules. 2023;28(4):1611.
17. Wang T, Kong S, Tao M, Ju S. The potential role of RNA N6-methyladenosine in Cancer progression. Mol Cancer. 2020;19:1-18.
18. Zeng C, Huang W, Li Y, Weng H. Roles of METTL3 in cancer: mechanisms and therapeutic targeting. J Hematol Oncol. 2020;13(1):117.
19. Zhou X, Chai K, Zhu H, Luo C, Zou X, Zou J, et al. The role of the methyltransferase METTL3 in prostate cancer: a potential therapeutic target. BMC cancer. 2024;24(1):8.
20. Snyder NA, Silva GM. Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response. J Biol Chem. 2021;297(3).
21. Dewson G, Eichhorn P, Komander D. Deubiquitinases in cancer. Nat Rev Cancer. 2023;23(12):842-62.
22. Tao L, Liu X, Jiang X, Zhang K, Wang Y, Li X, et al. USP10 as a Potential Therapeutic Target in Human Cancers. Genes-Basel. 2022;13(5):831.
23. Ye Z, Chen J, Huang P, Xuan Z, Zheng S. Ubiquitin-specific peptidase 10, a deubiquitinating enzyme: Assessing its role in tumor prognosis and immune response. Front Oncol. 2022;12:990195.
24. Liu X, Chen B, Chen J, Su Z, Sun S. Deubiquitinase ubiquitin-specific peptidase 10 maintains cysteine rich angiogenic inducer 61 expression via Yes1 associated transcriptional regulator to augment immune escape and metastasis of pancreatic adenocarcinoma. Cancer Sci. 2022;113(5):1868-79.
25. Shore ND, Morgans AK, Ryan CJ. Resetting the Bar of Castration Resistance - Understanding Androgen Dynamics in Therapy Resistance and Treatment Choice in Prostate Cancer. Clin Genitourin Canc. 2021;19(3):199-207.
26. Wagle MC, Castillo J, Srinivasan S, Holcomb T, Yuen KC, Kadel EE, et al. Tumor Fusion Burden as a Hallmark of Immune Infiltration in Prostate Cancer. Cancer Immunol Res. 2020;8(7):844-50.
27. Wang S, Gao S, Li Y, Qian X, Luan J, Lv X. Emerging Importance of Chemokine Receptor CXCR4 and Its Ligand in Liver Disease. Front Cell Dev Biol. 2021;9:716842.
28. Yang H, Zhang Q, Xu M, Wang L, Chen X, Feng Y, et al. CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer. 2020;19(1):41.
29. Deng LJ, Deng WQ, Fan SR, Chen MF, Qi M, Lyu WY, et al. m6A modification: recent advances, anticancer targeted drug discovery and beyond. Mol Cancer. 2022;21(1):52.
30. Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Tar. 2021;6(1):74.
31. Wang Q, Chen C, Ding Q, Zhao Y, Wang Z, Chen J, et al. METTL3-mediated m(6)A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut. 2020;69(7):1193-205.
32. Ni Z, Sun P, Zheng J, Wu M, Yang C, Cheng M, et al. JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA. Cancer Res. 2022;82(9):1789-802.
33. Guo J, Zhao J, Sun L, Yang C. Role of ubiquitin specific proteases in the immune microenvironment of prostate cancer: A new direction. Front Oncol. 2022;12:955718.
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| Issue | Articles in Press | |
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| Keywords | ||
| Castration-resistant prostate neoplasms CXCR4 receptor METTL3 protein USP10 protein | ||
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