The Deubiquitinase USP4 Stabilizes Twist1 Protein to Promote Lung Cancer Cell Stemness

Abstract

Lung cancer stem cells (CSCs) play a pivotal role in tumor development, drug resistance, metastasis and recurrence of lung cancer. Thus, it is of great importance to study the mechanism by which CSCs are regulated. In this study, we demonstrate that the deubiquitinase USP4 is critically important in promoting lung cancer stemness. Silencing of USP4 leads to reduction of Oct4 and Sox2 expression, decreased CD133+ cell population and inhibition of tumorsphere formation. Conversely, ectopic expression of USP4 significantly enhances lung cancer cell stemness, which is effectively rescued by simultaneous silencing of Twist1. Mechanistically, we identified USP4 as a novel deubiquitinase of Twist1. USP4 binds to, deubiquitinates and stabilizes Twist1 protein. Furthermore, we show that USP4 expression is elevated in human lung cancer specimens and is positively correlated with Twist1 expression. High expression of USP4/Twist1 is associated with poor clinical outcomes of lung cancer patients. Together, this study highlights an important role for USP4 in lung cancer stemness and suggests USP4 as a potential target for lung cancer diagnosis and treatment.

What deubiquitinating enzymes, oncogenes, and tumor suppressors actually do: Are current assumptions supported by patient outcomes?

“…[ 45 ] USP4 was also recently shown to promote lung stem cell properties through stabilization of Twist1; elevated levels of both USP4 and Twist1 were associated with reduced survival by Kaplan–Meier analysis. [ 46 ] In a figure that presented survival curves for a variety of cancer types elevated USP4 expression in the lung was associated with improved outcomes, whereas it was associated with reduced survival in other types including adrenocortical, kidney, and pancreatic cancers. [ 47 ]…”

SOX2-Upregulated microRNA-30e Promotes the Progression of Esophageal Cancer via Regulation of the USP4/SMAD4/CK2 Axis

“… 39 A recent work uncovers a positive correlation between USP4 expression and SOX2 expression in lung cancer. 40 However, our study revealed an adverse relationship between them, maybe due to the difference of the study subjects, laboratory environment, and the detection methods used.…”

Identify specific gene pairs for subarachnoid hemorrhage based on wavelet analysis and genetic algorithm

“…HR23A and HR23B are human orthologs of the yeast Rad23 (HR23) protein. Studies have shown that HR23A critically regulates the expression of Twist1 protein [ 25 ] and Chk1 protein and plays a vital role in cell functions (such as cell cycle progression, immunity, and stress response). Human HR23A protein has been shown to help control the stability and transcriptional activity of p53 [ 26 ].…”