SET-domain containing 2 (SETD2) is a histone methyltransferase and an epigenetic modifier with oncogenic functionality. In the current study, we investigated the potential prognostic role of SETD2 in prostate cancer. A cohort of 202 patients’ samples was assembled on tissue microarrays (TMAs) containing incidental, advanced, and castrate-resistant CRPCa cases. Our data showed significant elevated SETD2 expression in advanced and castrate-resistant disease (CRPCa) compared to incidental cases (2.53 ± 0.58 and 2.21 ± 0.63 vs. 1.9 ± 0.68;p< 0.001, respectively). Interestingly, the mean intensity of SETD2 expression in deceased vs. alive patients was also significantly different (2.31 ± 0.66 vs. 2 ± 0.68;p= 0.003, respectively). Overall, high SETD2 expression was found to be considered high risk and was significantly associated with poor prognosis and worse overall survival (OS) (HR 1.80; 95% CI: 1.28–2.53,p= 0.001) and lower cause specific survival (CSS) (HR 3.14; 95% CI: 1.94–5.08,p< 0.0001). Moreover, combining high-intensity SETD2 with PTEN loss resulted in lower OS (HR 2.12; 95% CI: 1.22–3.69,p= 0.008) and unfavorable CSS (HR 3.74; 95% CI: 1.67–8.34,p= 0.001). Additionally, high SETD2 intensity with ERG positive expression showed worse prognosis for both OS (HR 1.99, 95% CI 0.87–4.59;p= 0.015) and CSS (HR 2.14, 95% CI 0.98–4.68,p= 0.058). We also investigated the protein expression database TCPA, and our results showed that high SETD2 expression is associated with a poor prognosis. Finally, we performed TCGA PRAD gene set enrichment analysis (GSEA) data for SETD2 overexpression, and our data revealed a potential association with pathways involved in tumor progression such as the AMPK signaling pathway, the cAMP signaling pathway, and the PI3K-Akt signaling pathway, which are potentially associated with tumor progression, chemoresistance, and a poor prognosis.
含有SET结构域蛋白2（SETD2）是一种组蛋白甲基转移酶，兼具表观遗传修饰功能与致癌特性。本研究旨在探讨SETD2在前列腺癌中的潜在预后价值。我们通过组织芯片技术构建了包含偶发性、进展期及去势抵抗性前列腺癌病例的202例患者样本队列。数据显示，与偶发性病例相比，进展期及去势抵抗性前列腺癌中SETD2表达显著升高（分别为2.53±0.58和2.21±0.63 vs. 1.9±0.68；p<0.001）。值得注意的是，死亡患者与存活患者的SETD2表达平均强度也存在显著差异（分别为2.31±0.66 vs. 2±0.68；p=0.003）。总体而言，高SETD2表达被判定为高风险因素，与不良预后及较差的总生存期显著相关（风险比1.80；95%置信区间：1.28-2.53，p=0.001），同时导致更低的病因特异性生存率（风险比3.14；95%置信区间：1.94-5.08，p<0.0001）。此外，高强度SETD2表达与PTEN缺失联合作用会进一步降低总生存期（风险比2.12；95%置信区间：1.22-3.69，p=0.008）并恶化病因特异性生存（风险比3.74；95%置信区间：1.67-8.34，p=0.001）。当高强度SETD2与ERG阳性表达共存时，总生存期（风险比1.99，95%置信区间0.87-4.59；p=0.015）和病因特异性生存（风险比2.14，95%置信区间0.98-4.68，p=0.058）均呈现更差预后趋势。通过分析TCPA蛋白质表达数据库，我们发现高SETD2表达与不良预后存在关联。最后，基于TCGA前列腺癌数据集进行的基因集富集分析显示，SETD2过表达可能通过AMPK信号通路、cAMP信号通路及PI3K-Akt信号通路等与肿瘤进展相关的途径，潜在影响肿瘤进展、化疗耐药及不良预后。
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