# USP20 competitively binds to STUB1 to enhance CTSL expression and promote epithelial‐mesenchymal transition in head and neck squamous cell carcinoma

## TL;DR

This study shows how USP20 helps a protein called CTSL become more stable, which makes head and neck cancer more aggressive and resistant to treatment.

## Contribution

The study identifies USP20 as a new regulator of CTSL through competitive binding with STUB1, offering a potential target for treating metastatic HNSCC.

## Key findings

- USP20 deubiquitinates and stabilizes CTSL, promoting cancer progression.
- USP20 competes with STUB1 for CTSL binding, enhancing tumor malignancy.
- Targeting USP20 increases cancer cell sensitivity to chemotherapy drugs like cisplatin and paclitaxel.

## Abstract

Metastatic head and neck squamous cell carcinoma (mHNSCC) poses a significant threat to patient survival. Previous studies have identified cathepsin L (CTSL) as a key driver of tumourigenesis, metastasis and chemoresistance. However, the regulatory mechanisms underlying CTSL expression remain poorly understood.

A specific deubiquitinase responsible for CTSL expression was identified through treatment with broad‐spectrum deubiquitinase inhibitors and mass spectrometry analysis. The colocalization of CTSL and USP20 in the cytoplasm was examined using confocal microscopy. The effects of CTSL or USP20 depletion on tumour biological behaviour were evaluated through various in vitro and in vivo assays.

We identified USP20 as a specific deubiquitinase of CTSL. USP20 mediates the deubiquitination and stabilization of CTSL, thereby promoting epithelial‐to‐mesenchymal transition and cancer stem cell renewal, ultimately enhancing metastatic potential and chemoresistance. Notably, USP20 competes with STUB1 for CTSL binding, further driving the malignant phenotype of HNSCC. Analysis of clinical samples revealed that both CTSL and USP20 are highly expressed in metastatic HNSCC tissues, with a positive correlation between their expression levels.

Our study reveals a novel mechanism in which USP20 competitively interacts with STUB1 to stabilize CTSL and promote tumour progression. These findings provide preclinical evidence supporting USP20 as a potential therapeutic target for overcoming metastasis and chemotherapy resistance in HNSCC.

USP20 deubiquitinates and stabilizes CTSL.STUB1 promotes CTSL ubiquitination and degradation.USP20 competitively binds to CTSL in competition with STUB1.Targeting USP20 sensitizes cancer cells to cisplatin or paclitaxel.

USP20 deubiquitinates and stabilizes CTSL.

STUB1 promotes CTSL ubiquitination and degradation.

USP20 competitively binds to CTSL in competition with STUB1.

Targeting USP20 sensitizes cancer cells to cisplatin or paclitaxel.

USP20 deubiquitinates and stabilizes CTSL.STUB1 promotes CTSL ubiquitination and degradation.USP20 competitively binds to CTSL in competition with STUB1.Targeting USP20 sensitizes cancer cells to cisplatin or paclitaxel.

USP20 deubiquitinates and stabilizes CTSL.

STUB1 promotes CTSL ubiquitination and degradation.

USP20 competitively binds to CTSL in competition with STUB1.

Targeting USP20 sensitizes cancer cells to cisplatin or paclitaxel.