Mengdi Li, Yuting Lin, Jiayu Wang, He Yang, Danhui Ma, Ye Tian, Yi Wang, Liu Yang, Umar Farooq, Yinyin Wang, Fangli Ren, Jian Sheng, Guoqing Zhang, Liang Chen, Jun Li, Xiangnan Li, Zhijie Chang
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引用次数: 0
Abstract
Background: Despite advancements in EGFR- and KRAS-targeted therapies for lung adenocarcinoma (LUAD), novel targets are needed for patients unresponsive or resistant to current treatments. This study demonstrates the critical role of CREPT in modulating ERK-downstream gene transcription in LUAD progression. Methods: CREPT expression and function were investigated using human LUAD tissues, EGFR/KRAS mutant LUAD cell lines, and mouse models. Micro-CT was used to monitor tumor progression. Adeno-associated virus (AAV)-mediated CREPT depletion was employed as a therapeutic strategy. RNA sequencing and luciferase reporter assays identified differentially expressed genes (DEGs) and affected signaling pathways. Protein interactions and CDK9 occupancy were assessed using multiplex immunofluorescence, immunoprecipitation, and chromatin immunoprecipitation (ChIP). Results: CREPT overexpression correlated with poor LUAD patient survival and enhanced tumorigenesis in EGFR or KRAS mutant LUAD cells. CREPT deletion impaired LUAD initiation and progression in the CC10-rtTA;TetO-KRASG12D mouse model. Mechanistically, CREPT promoted CDK9 assembly with RNA polymerase II (RNAPII) following ERK activation, enhancing transcription of malignancy-related genes downstream of KRAS-ERK-Elk-1 signaling. CREPT depletion and the mutants R106A and S134A disrupting CREPT-RNAPII interaction reduced CDK9 occupancy at Elk-1 downstream gene promoters and their expression. Targeting CREPT in both CC10-rtTA;TetO-KRASG12D and xenograft mouse models resulted in tumor growth arrest. Furthermore, in a humanized mouse model, AAV-mediated CREPT silencing inhibited tumor progression and showed synergistic potential with pembrolizumab. Conclusion: Our findings highlight CREPT as a pivotal regulator of LUAD progression and suggest it could be a potential therapeutic target for patients with EGFR or KRAS mutations insensitive or resistant to targeted therapies.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.