# Deubiquitinase UCH-L1 confers paclitaxel resistance via stabilizing PKM2 to promote glycolysis in triple-negative breast cancer

## TL;DR

This study shows that UCH-L1 helps breast cancer cells resist chemotherapy by boosting sugar metabolism, suggesting new treatment strategies.

## Contribution

The novel finding is that UCH-L1 stabilizes PKM2 via deubiquitination, promoting glycolysis and chemoresistance in TNBC.

## Key findings

- UCH-L1 overexpression correlates with poor prognosis and chemotherapy resistance in TNBC.
- UCH-L1 stabilizes PKM2 by removing K48-linked ubiquitination, enhancing glycolysis.
- Inhibiting the UCH-L1/PKM2 axis increases sensitivity to paclitaxel in resistant TNBC cells.

## Abstract

Resistance to paclitaxel-based chemotherapy represents a major clinic challenge in triple-negative breast cancer (TNBC). Insights on the regulation genes of chemoresistance and underlying mechanisms in TNBC are waiting for in-depth investigation to address the current treatment bottlenecks. In this study, we identified that ubiquitin carboxyl terminal hydrolase-L1 (UCH-L1) was preferentially overexpressed in TNBC and correlated with worse prognosis as well as poor response to chemotherapy. Upregulation of UCH-L1 attenuated the inhibitory effect of paclitaxel on tumor cells through modulating the aerobic glycolysis, while knockdown of UCH-L1 increased the responsiveness of TNBC cells to the drug both in vitro and in vivo. Coimmunoprecipitation results revealed that the N terminal of UCH-L1 interacts with the C-terminal domain of pyruvate kinase M2 (PKM2). UCH-L1 stabilized PKM2 via removing K48-linked polyubiquitination of PKM2 protein at K498, and thereby promoting glycolysis. Moreover, the expression levels of UCH-L1 and PKM2 were elevated in paclitaxel-resistant TNBC cells, and inhibition of UCH-L1/PKM2 axis-mediated glycolysis markedly sensitized the cells to paclitaxel treatment. Meanwhile, high expression of PKM2 was associated with shorter overall survival in TNBC patients who received chemotherapy. Clinically, PKM2 expression is positively correlated with the expression of UCH-L1 in TNBC tissues. In conclusion, our study reveals that high-expressed UCH-L1 was one of the biomarkers predicting and determining chemosensitivities of TNBC by advancing the cleavage of K48-linked polyubiquitin chains from PKM2 and enhancing glycolysis, and suggests that targeting UCH-L1/PKM2 axis holds great promise for reversing chemoresistance.