KCA
Search
- Page Path
- HOME > Search
Original Article
- Lung and Thoracic cancer
- miR-4487 Enhances Gefitinib-Mediated Ubiquitination and Autophagic Degradation of EGFR in Non-Small Cell Lung Cancer Cells by Targeting USP37
- Mi Seong Kim, So Hui Kim, Sei Hoon Yang, Min Seuk Kim
- Cancer Res Treat. 2022;54(2):445-457. Published online August 3, 2021
- DOI: https://doi.org/10.4143/crt.2021.622
-
Abstract
PDF
PubReader
ePub - Purpose
With the identification of epidermal growth factor receptor (EGFR) mutations in non–small cell lung cancer (NSCLC) cells, EGFR–tyrosine kinase inhibitors (TKIs) are being used widely as the first-line of treatment in NSCLC. These inhibitors block auto-phosphorylation of activated EGFR by competing with ATP binding and mediate EGFR degradation independent of exogenous epidermal growth factor, which is associated with the mutation variants of EGFR. However, the precise mechanisms underlying the TKI-mediated EGFR degradation are still unclear.
Materials and Methods
To examine the physiological roles of miR-4487 and ubiquitin-specific peptidase 37 (USP37) in gefitinib-mediated EGFR degradation in NSCLC cells, multiple NSCLC cell lines were applied. The level of EGFR expression, apoptosis marker and autophagic flux were determined by western blot. Expression level of miR-4487 and cell cycle arrest was analyzed by TaqMan assay and flow cytometry respectively.
Results
We found that gefitinib mediates EGFR degradation under normal culture conditions, and is dependent on autophagic flux and the mutation variants of EGFR. Gefitinib reduced expression levels of USP37, which mediated EGFR degradation similar to gefitinib. Our results also showed a gefitinib-mediated increase in endogenous miR-4487 level and presented evidence for the direct targeting of USP37 by miR-4487, resulting in the sequential enhancement of ubiquitination, autophagy, and EGFR degradation. Thus, the depletion of USP37 and overexpression of miR-4487 led to an increase in gefitinib-mediated apoptotic cell death.
Conclusion
These data suggest that miR-4487 is a potential target for treating NSCLC, and miR-4487/USP37-regulated EGFR degradation is a determinant for developing gefitinib resistance. -
Citations
Citations to this article as recorded by
- Identification of Raptor and GLI1 as USP37 substrates highlight its context-specific function in medulloblastoma cells
Ashutosh Singh, Donghang Cheng, Amanda R. Haltom, Yanwen Yang, Tara Dobson, Rashieda Hatcher, Veena Rajaram, Vidya Gopalakrishnan
Oncogene.2026; 45(4): 521. CrossRef - The ubiquitination–autophagy axis in cancer therapy resistance: mechanistic insights and therapeutic opportunities
Hengrui Zhang, Hanxi Yan, Yulin Liu, Anqi Zeng, Linjiang Song
Frontiers in Pharmacology.2026;[Epub] CrossRef - Epigenetic code underlying EGFR-TKI resistance in non-small cell lung cancer: Elucidation of mechanisms and perspectives on therapeutic strategies
XiaoYu Yao, Chundi Gao, Changgang Sun, Zhe-Sheng Chen, Jing Zhuang
Drug Discovery Today.2025; 30(3): 104321. CrossRef - Deubiquitination of epidermal growth factor receptor by ubiquitin-specific peptidase 54 enhances drug sensitivity to gefitinib in gefitinib-resistant non-small cell lung cancer cells
Mi Seong Kim, Min Seuk Kim, Chien-Feng Li
PLOS ONE.2025; 20(4): e0320668. CrossRef - MicroRNAs as Sensitizers of Tyrosine Kinase Inhibitor Resistance in Cancer: Small Molecule Partnerships
Alma D. Campos-Parra, David Sánchez-Marín, Víctor Acevedo-Sánchez
Pharmaceuticals.2025; 18(4): 492. CrossRef - Mechanistic Insights and Therapeutic Potentials of Ubiquitin‐Proteasome System in Non‐Small Cell Lung Cancer
Guangyao Zhou, Jiaxiong Tan, Pengpeng Zhang, Zhaokai Zhou, Lianmin Zhang, Zhenfa Zhang
Cell Proliferation.2025;[Epub] CrossRef - Exploring the potential function of high expression of ANAPC1 in regulating ubiquitination in hepatocellular carcinoma
Yu-Xing Tang, Wei-Zi Wu, Sheng-Sheng Zhou, Da-Tong Zeng, Guang-Cai Zheng, Rong-Quan He, Di-Yuan Qin, Wan-Ying Huang, Ji-Tian Chen, Yi-Wu Dang, Yu-Lu Tang, Bang-Teng Chi, Yan-Ting Zhan, Gang Chen
World Journal of Gastrointestinal Oncology.2025;[Epub] CrossRef - Autophagy-associated ncRNAs in lung cancer: From drug resistance to therapeutic targets
Ming Yu, Hanqing Li, Yin Wu, Ping Liu, Quangang Xu, Yi Zhang
International Journal of Biological Macromolecules.2025; 319: 145477. CrossRef - Bioinformatics based exploration of the anti-liver fibrosis mechanism of Pien Tze Huang via EGFR/JAK1/STAT3 pathway
Xiaoting Hong, Yonghua Ye, Chunfeng Lin, Miaolan Zheng, Fan Lin, Qing Xiong, Wei Xu, Huang Li, Yuqin Zhang, Haiyin Zheng
Frontiers in Immunology.2025;[Epub] CrossRef - The significance of the crosstalk between ubiquitination or deubiquitination and ncRNAs in non-small cell lung cancer
Yiyang Sun, Ping He, Li Li, Xue Ding
Frontiers in Oncology.2023;[Epub] CrossRef - Lung adenocarcinoma cell-derived exosomes promote M2 macrophage polarization through transmission of miR-3153 to activate the JNK signaling pathway
L Xu, L Wang, R Yang, T Li, X Zhu
Human Molecular Genetics.2023; 32(13): 2162. CrossRef - The potential role of miRNAs in the pathogenesis of salivary gland cancer – A Focus on signaling pathways interplay
Ahmed I. Abulsoud, Shereen Saeid Elshaer, Ahmed A. El-Husseiny, Doaa Fathi, Nourhan M. Abdelmaksoud, Sherif S. Abdel Mageed, Aya Salman, Mohamed Bakr Zaki, Hesham A. El-Mahdy, Ahmed Ismail, Elsayed G.E. Elsakka, Mai A. Abd-Elmawla, Hussein M. El-Husseiny,
Pathology - Research and Practice.2023; 247: 154584. CrossRef
- Identification of Raptor and GLI1 as USP37 substrates highlight its context-specific function in medulloblastoma cells
- 9,725 View
- 208 Download
- 14 Web of Science
- 12 Crossref
First
Prev
