Dung Dao

Background: Bladder cancer, primarily affecting the urothelial cell layer, can be divided into two types: non-muscle invasive (NMIBC) and muscle-invasive (MIBC).¹ It is the 4th most common malignancy in males and 11th in females, with about 550,000 new cases, and a high frequency of recurrence.^1,2,3 Risk factors include smoking, chemical exposure, and age.^3,4 Treatment includes immunotherapies, such as Bacille Calmette-Guérin for NMIBC and cystectomy for MIBC. However, the global shortage of Bacille Calmette-Guérin and high recurrence rates pose challenges.^3,5 KDM6A gene mutations are frequently seen across many types of bladder cancer.^4,5 KDM6A gene mutations that reduce its expression can play a role in hindering immune response efficiency. Understanding the role of KDM6A gene mutations in anti-tumor progression remains a key research gap and potential therapeutic target.^1,2

Objective: This narrative review explores into the mechanisms through which KDM6A gene mutations contribute to the promotion of bladder cancer.

Search Methods: An online search in the PubMed database was conducted from 2018-2023 using the keywords: “bladder cancer”, “immune response”, “KDM6A”, “gene expression”

Results: Studies show that KDM6A mutations show high frequency in urothelial carcinomas, but their direct role in bladder cancer is uncertain.^4,6 It regulates the anti-tumor immune response and plays role in Rac-1 inhibition, cytokine/chemokine pathways, and M2 macrophage polarization.^2,4,5,7,8 Studies indicate that KDM6A plays an antitumor role by inhibiting Rac1 from the activated transcription of the Rho GDP dissociation inhibitor beta (ARHGDIB)⁷. ARHGDIB is a downstream effector of KDM6A expression as they both play a role as tumor metastasis suppressor.⁷ KDM6A mutation group showed lower infiltration levels of macrophages, CD8+ T Cells, neutrophils and resting dendritic cells with there being a significant difference in infiltration of Naïve B cell, M2 Macrophage, and resting Mast Cells when comparing wild type and KDM6A knock-out cells.² KDM6A mutations downregulates immune response signaling pathways in bladder cancer, such as T-Cell Receptor, B-Cell Receptor, and Chemokine signaling.² Results indicated mutation in KDM6A upregulated genes, the most being Ccl2, Il6, Cxcl1, in the KEGG chemokine signaling pathway, which mediated M2 macrophage polarization and STAT3 activation.⁴ This showed a positive correlation with disease pathogenesis.⁴ Western blot analysis revealed that while total Rac1 protein levels remained unchanged, overexpression of KDM6A decreased active Rac1 (Rac1-GTP) levels, whereas KDM6A knockdown led to an increase in active Rac1.⁷ Additionally, in T24 cells expressing wild-type KDM6A compared to a mutant variant, only the wild-type KDM6A was able to upregulate ARHGDIB expression at both protein and mRNA levels, indicating the loss of histone demethylase activity in the mutant.⁷

Conclusions: Studies indicate KDM6A gene regulates the anti-tumor response and prevents EZH2-mediated cell proliferation, Rac1 activation, and M2 macrophage polarization.^2,4,5,7,8 Mutations in KDM6A cause dysregulation in cell differentiation, increase inflammatory pathways and cell proliferation in Rac1 pathway, promoting cancer stem phenotypes.^2,4,5,7,8. KDM6A mRNA intravesical delivery showed promising signs for future clinical immunotherapy.⁹

Works Cited:

1. Lenis AT, Lec PM, Chamie K, Mshs Bladder Cancer: A Review. JAMA. 2020;324(19):1980-1991. doi:10.1001/jama.2020.17598
2. Chen X, Lin X, Pang G, Deng J, Xie Q, Zhang Significance of KDM6A mutation in bladder cancer immune escape. BMC Cancer. 2021 May 29;21(1):635. doi: 10.1186/s12885-021-08372-9. PMID: 34051747; PMCID: PMC8164329.
3. Dobruch J, Oszczudłowski Bladder Cancer: Current Challenges and Future Directions. Medicina. 2021; 57(8):749. https://doi.org/10.3390/medicina57080749
4. Kobatake K, Ikeda KI, Nakata Y, et Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction. Clin Cancer Res. 2020;26(8):2065-2079. doi:10.1158/1078-0432.CCR-19-2230
5. Koti M, Bivalacqua T, Black PC, et Adaptive Immunity in Genitourinary Cancers. Eur Urol Oncol. 2023;6(3):263-272. doi:10.1016/j.euo.2023.03.002
6. Qiu J-G, Shi D-Y, Liu X, Zheng X-X, Wang L, Li Q. Chromatin-regulatory genes served as potential therapeutic targets for patients with urothelial bladder carcinoma. J Cell Physiol. 2019; 234: 6976–6982. https://doi.org/10.1002/jcp.27440
7. Liu, , Cui, J., Zhao, Y. et al. KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1. Mol Cancer 20, 77 (2021). https://doi.org/10.1186/s12943-021-01369-9
8. Qiu H, Makarov V, Bolzenius JK, et KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer. Cancer Res. 2023;83(6):814-829. doi:10.1158/0008-5472.CAN-22-1444
9. Kong, N., Zhang, R., Wu, G., Sui, X., Wang, J., Kim, N. Y., Blake, S., De, D., Xie, T., Cao, , & Tao, W. (2022). Intravesical delivery of kdm6a-mrna via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer. Proceedings of theNational Academy of Sciences, 119(7). https://doi.org/10.1073/pnas.2112696119