Usp6nl, also named RN-tre, is a GTPase-activating protein functioning as a deubiquitinating enzyme, regulating endocytosis and signal transduction [3,4]. It is involved in multiple biological processes and is associated with various diseases. In the Wnt/β-catenin pathway, it has been shown to play a role in cell proliferation and cell cycle regulation [1].

In colorectal cancer, knockdown of Usp6nl in human CRC cell lines inhibited cell proliferation, induced G0/G1 cell cycle arrest, and prevented tumorigenicity in nude mice, associated with the prevention of the Wnt/β-catenin pathway [1]. In triple-negative breast cancer, RNA interference-mediated knockdown of Usp6nl inhibited cell growth, motility, and epithelial-mesenchymal transitions (EMT) [2]. In breast cancer, high levels of Usp6nl delayed endocytosis and degradation of the EGFR, causing chronic AKT activation, increased aerobic glycolysis, and promoting cell proliferation, while its depletion impaired cell proliferation in cells with high Usp6nl levels [3]. In glioblastoma, abrogation of Usp6nl reversed the oncogenic and drug-resistant properties of GBM cells and resensitized them to temozolomide by enhancing autophagy and reducing the DNA damage repair response [4].

In conclusion, Usp6nl is a key regulator in multiple cellular processes. Its dysregulation is implicated in various cancers, such as colorectal, breast, and glioblastoma. The use of gene knockdown (a form of functional equivalent to KO in cell-based models) in these studies has revealed its role in promoting cancer cell proliferation, survival, and drug resistance, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Sun, Kang, He, Song-Bing, Yao, Yi-Zhou, Zong, Ming-Hui, Chen, Ji-Xiang. 2019. Tre2 (USP6NL) promotes colorectal cancer cell proliferation via Wnt/β-catenin pathway. In Cancer cell international, 19, 102. doi:10.1186/s12935-019-0823-0. https://pubmed.ncbi.nlm.nih.gov/31015802/

2. Ma, Teng, Liu, Huaidong, Liu, Yan, Song, Lu, Zhang, Lin. 2020. USP6NL mediated by LINC00689/miR-142-3p promotes the development of triple-negative breast cancer. In BMC cancer, 20, 998. doi:10.1186/s12885-020-07394-z. https://pubmed.ncbi.nlm.nih.gov/33054738/

3. Avanzato, Daniele, Pupo, Emanuela, Ducano, Nadia, Sapino, Anna, Lanzetti, Letizia. 2018. High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis. In Cancer research, 78, 3432-3444. doi:10.1158/0008-5472.CAN-17-3018. https://pubmed.ncbi.nlm.nih.gov/29691252/

4. Su, I-Chang, Su, Yu-Kai, Chuang, Hao-Yu, Huang, Hui-Chuan, Lin, Chien-Min. 2022. Ubiquitin-Specific Protease 6 n-Terminal-like Protein (USP6NL) and the Epidermal Growth Factor Receptor (EGFR) Signaling Axis Regulates Ubiquitin-Mediated DNA Repair and Temozolomide-Resistance in Glioblastoma. In Biomedicines, 10, . doi:10.3390/biomedicines10071531. https://pubmed.ncbi.nlm.nih.gov/35884836/