Abstract 2010: TRIM27 Interacts with KLF12 to regulate L1CAM expression, influencing cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma

Abstract

Abstract Esophageal squamous cell carcinoma (ESCC) accounts for 85% of cases of esophageal cancer worldwide and is the predominant form of esophageal cancer in Asia. A significant number of patients with ESCC are diagnosed at an advanced stage, resulting in poor prognosis. Cisplatin resistance and cancer metastasis are the main clinical challenges in the treatment of advanced ESCC. KLF12 has been extensively characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and NK cell proliferation. However, the precise 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, cancer metastasis and recruitment of regulatory T cells (Tregs) in ESCC cell lines. Mechanistically, KLF12 binds to the promoters of L1CAM and represses its expression. Depletion of L1CAM abrogates cisplatin resistance, cancer metastasis, and Treg recruitment caused by KLF12 loss. Moreover, the E3 ubiquitin ligase 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 has firstly elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC, and targeting KLF12/L1CAM axis may be a promising approach for ESCC treatment. Citation Format: Hao Zhang, Chunxiang Li, Jie He. TRIM27 Interacts with KLF12 to regulate L1CAM expression, influencing cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2010.