Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China; Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha 410008, China.
Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China.
Cell Rep. 2023 Dec 26;42(12):113477. doi: 10.1016/j.celrep.2023.113477. Epub 2023 Nov 20.
Targeting lysine-specific histone demethylase 1A (LSD1) can improve tumor immunogenicity of poorly immunogenic tumors, such as non-small cell lung cancer (NSCLC), with elevated T cell infiltration and sensitize tumors to anti-PD-1 therapy. However, the lack of reliable biomarkers limits utilization of LSD1 inhibitors in cancer therapy. Here, we identify an E3 ligase, Trim35, as an effective biomarker for high activity of LSD1 to predict prognosis of LSD1-targeted therapy as well as immunotherapy. Mechanistically, Trim35 represses LSD1 demethylase activity by mediating K63 ubiquitination at lysine site 422 of LSD1. Suppressed LSD1 activity facilitates ERGIC1 transcription, followed by autophagy inhibition and IFNGR1 stabilization to activate IFN-γ signaling, leading to increased MHC class I expression and immune surveillance of NSCLC cells. Furthermore, combinational use of an LSD1 inhibitor and anti-PD-1 therapy can significantly eradicate poorly immunogenic lung cancer with low Trim35. These findings strongly suggest that Trim35 is a promising biomarker for prediction of immunotherapy outcome in NSCLC.
靶向赖氨酸特异性组蛋白去甲基化酶 1A（LSD1）可以提高低免疫原性肿瘤（如非小细胞肺癌 [NSCLC]）的肿瘤免疫原性，增加 T 细胞浸润，并使肿瘤对抗 PD-1 治疗敏感。然而，缺乏可靠的生物标志物限制了 LSD1 抑制剂在癌症治疗中的应用。在这里，我们鉴定出一种 E3 连接酶 Trim35 作为 LSD1 高活性的有效生物标志物，可预测 LSD1 靶向治疗和免疫治疗的预后。在机制上，Trim35 通过介导 LSD1 赖氨酸 422 位的 K63 泛素化来抑制 LSD1 去甲基酶活性。抑制 LSD1 活性促进 ERGIC1 转录，随后抑制自噬并稳定 IFNGR1 以激活 IFN-γ 信号，导致 MHC 类 I 表达增加和 NSCLC 细胞的免疫监视。此外，LSD1 抑制剂与抗 PD-1 治疗联合使用可以显著消除低 Trim35 的低免疫原性肺癌。这些发现强烈表明，Trim35 是预测 NSCLC 免疫治疗结果的有前途的生物标志物。
