Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
School of Pharmaceutical Science, Wenzhou Medical University, China.
Mol Oncol. 2023 Dec;17(12):2659-2674. doi: 10.1002/1878-0261.13512. Epub 2023 Sep 2.
Recent studies have pointed to the role of Krüpple-like factor 12 (KLF12) in cancer-associated processes, including cancer proliferation, apoptosis, and metastasis. However, the role of KLF12 in tumor immunity remains obscure. Here, we found that KLF12 expression was significantly higher in non-small cell lung cancer (NSCLC) cells with higher programmed death-ligand 1 (PD-L1) expression. Additionally, a positive correlation between KLF12 and PD-L1 was observed in clinical patient tumor tissues. By chromatin immunoprecipitation (ChIP) analysis, KLF12 was identified to bind to the CACCC motif of the PD-L1 promoter. Overexpression of KLF12 promoted PD-L1 transcription, whereas silencing of KLF12 inhibited PD-L1 transcription. Furthermore, signal transducer and activator of transcription 1 (STAT1)- and STAT3-triggered PD-L1 transcription was abolished in the absence of KLF12, and KLF12 knockdown weakened the binding of STAT1 and STAT3 to the PD-L1 promoter. Mechanistically, KLF12 physically interacted with P300, a histone acetyltransferase. In addition, KLF12 silencing reduced P300 binding to the PD-L1 promoter, which subsequently caused decreased acetylation of histone H3. PD-L1 transcription driven by KLF12 overexpression was eliminated by EP300 silencing. In immunocompetent mice, KLF12 knockout inhibited tumor growth and promoted infiltration of CD8 T cells. However, this phenomenon was not observed in immunodeficient mice. Overall, this study reveals KLF12-mediated transcriptional regulation of PD-L1 in NSCLC; targeting KLF12 may be a potential therapeutic strategy for NSCLC.
最近的研究表明，Krüpple 样因子 12（KLF12）在癌症相关过程中发挥作用，包括癌症增殖、凋亡和转移。然而，KLF12 在肿瘤免疫中的作用仍然不清楚。在这里，我们发现，在程序性死亡配体 1（PD-L1）表达较高的非小细胞肺癌（NSCLC）细胞中，KLF12 的表达明显更高。此外，在临床患者肿瘤组织中观察到 KLF12 与 PD-L1 之间存在正相关。通过染色质免疫沉淀（ChIP）分析，鉴定到 KLF12 与 PD-L1 启动子的 CACCC 基序结合。KLF12 的过表达促进了 PD-L1 的转录，而 KLF12 的沉默则抑制了 PD-L1 的转录。此外，在缺乏 KLF12 的情况下，信号转导和转录激活因子 1（STAT1）和 STAT3 触发的 PD-L1 转录被废除，而 KLF12 的敲低削弱了 STAT1 和 STAT3 与 PD-L1 启动子的结合。在机制上，KLF12 与组蛋白乙酰转移酶 P300 发生物理相互作用。此外，KLF12 沉默减少了 P300 与 PD-L1 启动子的结合，从而导致组蛋白 H3 的乙酰化减少。通过 KLF12 过表达驱动的 PD-L1 转录被 EP300 沉默消除。在免疫功能正常的小鼠中，KLF12 敲除抑制肿瘤生长并促进 CD8 T 细胞浸润。然而，在免疫缺陷小鼠中没有观察到这种现象。总之，这项研究揭示了 KLF12 在 NSCLC 中对 PD-L1 的转录调控作用；靶向 KLF12 可能是 NSCLC 的一种潜在治疗策略。
