Yang Qingyuan, Wei Shiyin, Qiu Cen, Han Chenjie, Du Zunguo, Wu Ning
Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Affiliated Hospital of Youjiang Medical University for Nationalities, Baise City, Guangxi, China.
Cell Death Dis. 2024 Dec 6;15(12):882. doi: 10.1038/s41419-024-07275-4.
Histone lysine demethylase LSD1, also known as KDM1A, has been found to regulate multiple cancer hallmarks since it was first identified in 2004. Recently, it has emerged as a promising target for stimulating anti-tumor immunity, specifically boosting T cell activity. However, it remains unclear whether and how it remodels the tumor microenvironment to drive oncogenic processes in esophageal squamous cell carcinoma (ESCC). In this study, protein levels in ESCC tissues were evaluated by immunostaining of tissue microarrays. Cell growth was assessed by colony formation assays in vitro and subcutaneous xenograft models in vivo. High-throughput transcriptomics and spatial immune proteomics were performed using bulk RNA sequencing and digital spatial profiling techniques, respectively. Epigenetic regulation of RAD51 by methylated histone proteins was analyzed using chromatin immunoprecipitated quantitative PCR assays. Finally, our clinical data indicate that KDM1A precisely predicts the overall survival of patients with early-stage ESCC. Inhibition of KDM1A blocked the growth of ESCC cells in vitro and in vivo. Mechanistically, our transcriptomics and spatial immune proteomics data, together with rescue assays, demonstrated that KDM1A specifically removes methyl residues from the histone protein H3K9me2, a transcription repressive marker, thus reducing its enrichment at the promoter of RAD51 to epigenetically reactivate its transcription. Additionally, it significantly inhibits the expression of NF-κB signaling-dependent proinflammatory genes IL-6 and IL-1B through RAD51, thus blocking the STING-associated anti-tumor immunity in stromal tumor-infiltrating lymphocytes (sTIL). Overall, our findings not only indicate that KDM1A is a promising target for ESCC patients at early stages but also provide novel mechanistic insights into its spatial regulation of STING-associated anti-tumor immunity in sTILs to drive the oncogenic processes in ESCC. The translation of these findings will ultimately guide more appropriate combinations of spatial immunotherapies with KDM1A inhibitors to improve the overall survival of specific subgroups in ESCC.
组蛋白赖氨酸去甲基化酶LSD1，也称为KDM1A，自2004年首次被发现以来，已被证实可调控多种癌症特征。最近，它已成为刺激抗肿瘤免疫、特别是增强T细胞活性的一个有前景的靶点。然而，尚不清楚它是否以及如何重塑肿瘤微环境以驱动食管鳞状细胞癌（ESCC）的致癌过程。在本研究中，通过组织微阵列免疫染色评估ESCC组织中的蛋白质水平。通过体外集落形成试验和体内皮下异种移植模型评估细胞生长。分别使用批量RNA测序和数字空间分析技术进行高通量转录组学和空间免疫蛋白质组学研究。使用染色质免疫沉淀定量PCR分析甲基化组蛋白对RAD51的表观遗传调控。最后，我们的临床数据表明，KDM1A能准确预测早期ESCC患者的总生存期。抑制KDM1A可阻断ESCC细胞在体外和体内的生长。从机制上讲，我们的转录组学和空间免疫蛋白质组学数据以及挽救试验表明，KDM1A特异性地从组蛋白H3K9me2上去除甲基残基，H3K9me2是一种转录抑制标记，从而减少其在RAD51启动子处的富集，以表观遗传方式重新激活其转录。此外，它通过RAD51显著抑制NF-κB信号依赖性促炎基因IL-6和IL-1B的表达，从而阻断基质肿瘤浸润淋巴细胞（sTIL）中与STING相关的抗肿瘤免疫。总体而言，我们的研究结果不仅表明KDM1A是早期ESCC患者的一个有前景的靶点，而且为其在sTIL中对与STING相关的抗肿瘤免疫的空间调控以驱动ESCC致癌过程提供了新的机制见解。这些研究结果的转化最终将指导KDM1A抑制剂与空间免疫疗法更合适的联合应用，以提高ESCC特定亚组的总生存期。
