This study elucidates the expression of KDM5D in male bladder cancer, its impact on prognosis, and the associated mechanisms. We found that KDM5D, a Y-linked gene, is underexpressed in male bladder cancer and is associated with metastasis and recurrence. This result suggests that KDM5D acts as a male-specific protective gene in bladder cancer, potentially leading to a better prognosis in males.
KDM5D is a gene involved in the regulation of epigenetics. Previous research has indicated that epigenetic alterations play a crucial role in the initiation and progression of tumors[7]. Epigenetic phenomena primarily encompass DNA methylation, RNA interference, and histone modification. Histones are divided into four core histones (H2A, H2B, H3, and H4), and these four core histones form an octamer that wraps around 146 bp of DNA, constituting the core nucleosome of chromosomes [8]. Histones are susceptible to methylation or demethylation modifications [9]. Aberrant histone demethylation can lead to excessive cell proliferation, consequently contributing to tumorigenesis. It has been demonstrated to be associated with numerous cancers [10–12]."。
KDM5D encodes lysine-specific demethylase (KDM5), a type of histone-modifying enzyme that counteracts lysine methylation [13]. These KDMs possess critical non-catalytic functions, including recruiting epigenetic modifiers and transcription factors to specific chromatin loci [14].The KDM5 family includes KDM5A, KDM5B, KDM5C, and KDM5D. The roles of the KDM5 family in the initiation and progression of different cancers vary: KDM5A is closely associated with breast cancer, prostate cancer, ovarian cancer, and small cell lung cancer [15–18]. The expression of KDM5B promotes the invasion and metastasis of non-small cell lung cancer [19]. KDM5C is highly expressed in prostate cancer and currently serves as a prognostic marker for prostate-specific antigen recurrence after radical prostatectomy [20]. On the other hand, KDM5D can inhibit the invasion and metastasis of prostate cancer and suppress gastric cancer metastasis by inhibiting epithelial-mesenchymal transition in male gastric cancer [6, 21]. However, there are no reported findings regarding the role of the KDM5 family in bladder cancer.
Our research has revealed that KDM5D plays a protective role in male bladder cancer, with lower rates of metastasis and recurrence observed when it is highly expressed. Through pathway enrichment analysis, we observed a significant enrichment of CD8+ T cells when KDM5D is highly expressed. Recently, Hani et al. demonstrated that LOY (Loss of Y chromosome) can promote tumor formation and growth by inducing the exhaustion of CD8+ T cells, evading adaptive immunity, and enhancing the effectiveness of immune checkpoint blockade (ICB) in tumors [22]. LOY is characterized by the loss or extreme downregulation of the Y chromosome, encoding KDM genes, with age, which serves as a risk marker for male cancer [23, 24]. While we have established a correlation between KDM5D and CD8+ T cells, the specific mechanisms remain to be further explored.
Thus, we can suppose that KDM5D may suppress tumor metastasis and recurrence in bladder cancer by enriching CD8+ T cells. However, in colon cancer, KDM5D can promote tumor metastasis by disrupting cancer cell adhesion properties and facilitating tumor immune evasion (5). This aligns with the observed gender disparities in colon and bladder cancer, where male colon cancer has a worse prognosis compared to females [25], while male bladder cancer exhibits a better prognosis [26, 27]. KDM5D exhibiting completely opposite effects in different cancers warrants further investigation and research.
Therefore, in order to further investigate the relationship between KDM5D and the immune system, we investigated the relationship between KDM5D and immune checkpoint inhibitors (ICIs) and found that KDM5D expression is negatively correlated with LAG3 and positively correlated with Siglec-15. Studies have reported that LAG3 can inhibit the activation of T cells by binding to its ligand MHC-II, thereby weakening immune cell attacks on tumor cells, potentially enabling tumor escape from immune surveillance and control, and promoting tumor growth and dissemination[28, 29]. Previous studies demonstrated that Siglec-15 inhibits antigen-specific T cell responses in vitro and in vivo, promoting tumor growth and spread [30, 31]. This result suggests that the interplay between KDM5D and immune checkpoints is complex and warrants further investigation.
It should be noted that a limitation of this study is that we did not investigate the impact of KDM5D overexpression on cell function, as well as the specific mechanisms by which KDM5D influences bladder cancer cell metastasis or recurrence. However, our findings are sufficient to demonstrate the expression of KDM5D in bladder cancer and its relationship with metastasis and recurrence. In the future, we will further explore the function of KDM5D in bladder cancer cells and its specific mechanisms affecting metastasis and recurrence.