Lee Je-Jung, Park In Ho, Kwak Man Sup, Rhee Woo Joong, Kim Songhee H, Shin Jeon-Soo
Department of Microbiology, Yonsei University College of Medicine, Seoul, South Korea.
Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, South Korea.
Cell Death Discov. 2021 Feb 8;7(1):28. doi: 10.1038/s41420-021-00409-z.
Although cellular senescence has emerged as a novel therapeutic concept in cancer, its underlying mechanisms remain unclear. High mobility group box 1 (HMGB1) and stimulator of interferon genes (STING) are involved in senescence. However, their interactions in senescence have not been reported. Therefore, in this study, we investigated the relationships between HMGB1 and STING in senescence in cancer and other cells. In mouse melanoma cells and several other cell lines, doxorubicin treatment induced senescence in an HMGB1-dependent manner. These responses were mediated by STING, and this function of STING was negatively regulated by the E3 ligase tripartite motif protein 30α (TRIM30α). We also found that HMGB1 bound to the TRIM30α promoter and then suppressed its expression by inhibiting its transcription, which enhanced STING-induced senescence. This mechanism was further mediated by signal transducer and activator of transcription 6 (STAT6) and p21. Overall, our findings demonstrated that HMGB1 orchestrated STING-STAT6-p21-mediated senescence by regulating TRIM30α as an alternative anticancer mechanism.
尽管细胞衰老已成为癌症治疗的一个新的治疗概念，但其潜在机制仍不清楚。高迁移率族蛋白B1（HMGB1）和干扰素基因刺激因子（STING）参与衰老过程。然而，它们在衰老过程中的相互作用尚未见报道。因此，在本研究中，我们研究了HMGB1与STING在癌症及其他细胞衰老中的关系。在小鼠黑色素瘤细胞和其他几种细胞系中，阿霉素处理以HMGB1依赖的方式诱导衰老。这些反应由STING介导，并且STING的这种功能受到E3连接酶三方基序蛋白30α（TRIM30α）的负调控。我们还发现，HMGB1与TRIM30α启动子结合，然后通过抑制其转录来抑制其表达，从而增强STING诱导的衰老。这一机制进一步由信号转导和转录激活因子6（STAT6）和p21介导。总体而言，我们的研究结果表明，HMGB1通过调节TRIM30α来协调STING-STAT6-p21介导的衰老，这是一种替代的抗癌机制。
