ZNF133 is a potent suppressor in breast carcinogenesis through dampening L1CAM, a driver for tumor cell invasion

Abstract

Background Because of the complexity and heterogeneity, therapeutic effect of breast cancer varies in each subtype, which is classified based on the molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2. Thus, novel comprehensive and precise molecular indicators in breast carcinogenesis are urgently in need. Methods The expression of ZNF133 in breast cancer tissues was detected by immunohistochemical staining. The interaction between KAP1 complex and ZNF133 was identified by affinity purification-coupled mass spectrometry. The regulatory mechanisms were validated by luciferase reporter assay and co-immunoprepitation. The target genes of ZNF133 was determinged by chromatin immunoprecipitation-based deep sequencing. Gain-or-loss-of-function assays were used to identify the function and underlying mechanisms of ZNF133 in breast cancer. Cancer cell proliferation, invasion, and tumorigenesis of breast cancer cells were analyzed using cell counting assays, colony formation, transwell, and xenograft tumor models. Results Here we report that ZNF133, a zinc-finger protein, is negatively associated with advanced pathological staging and poor survival of breast carcinomas. Moreover, ZNF133 is a transcription repressor, physically associated with the KAP1 complex and transcriptionally represses a cohort of genes including L1CAM that are critically involved in cell proliferation and motility. We demonstrate that the ZNF133/KAP1 complex inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo through dampening the transcription of L1CAM. Conclusion Our study ascertains the value of ZNF133 and L1CAM level in the diagnosis and prognosis of breast cancer, contributes to the deeper understanding of the regulation mechanism of ZNF133 for the first time, and provides a new therapeutic strategy and precise intervention target for breast cancer.

Development of a circHIPK3-based ceRNA network and identification of mRNA signature in breast cancer patients harboring BRCA mutation

“…MiRNA-876-3p exerts inhibitory effects on pancreatic adenocarcinoma cell growth and metastasis through regulating JAG2 ( Yang et al, 2018 ). L1CAM is a promotor for tumor invasion, whereas inhibition of L1CAM can suppress breast cancer aggressiveness and attenuate cisplatin resistance via modulating AKT signaling ( Li et al, 2022 ; Zhang, Shen & Guo, 2022b ). Additionally, miRNA-296-3p could inhibit HCC cell proliferation and invasion targeting MSL2 and functions as a tumor suppressor ( Li, An & Gao, 2021 ).…”