Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment.

中文翻译：

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KLF12与TRIM27相互作用通过调节L1CAM表达影响食管鳞癌顺铂耐药和癌转移


Krüppel 样因子 12 (KLF12) 已被定性为转录抑制因子，之前的研究已揭示其在血管生成、神经管缺陷和自然杀伤 (NK) 细胞增殖中的作用。然而，KLF12 对癌症治疗的贡献仍不清楚。在这里，我们发现KLF12在多种癌症类型中下调，并且KLF12下调促进食管鳞状细胞癌（ESCC）中的顺铂耐药和癌症转移。从机制上讲，KLF12 与 L1 细胞粘附分子 (L1CAM) 的启动子结合并抑制其表达。 L1CAM 的耗竭消除了由 KLF12 缺失引起的顺铂耐药性和癌症转移。此外，E3 泛素连接酶三联基序 27 (TRIM27) 与 KLF12 的 N 末端区域结合，并通过 K33 连接的多泛素化在 K326 处泛素化 KLF12。值得注意的是，TRIM27 缺失增强了 KLF12 的转录活性，从而抑制 L1CAM 表达。总体而言，我们的研究阐明了一种涉及 TRIM27、KLF12 和 L1CAM 的新型调控机制，该机制在 ESCC 顺铂耐药和癌症转移中发挥重要作用。针对这些基因可能是食管鳞癌治疗的一种有前途的方法。