# CSN6 Promotes Pancreatic Cancer Progression and Gemcitabine Resistance via Antagonizing DCAF1‐Mediated Ubiquitination of NPM1

## TL;DR

CSN6 helps pancreatic cancer grow and resist treatment by stabilizing NPM1, which boosts ribosome production and drug resistance.

## Contribution

This study reveals a novel mechanism by which CSN6 promotes pancreatic cancer progression and gemcitabine resistance via DCAF1-NPM1 interaction.

## Key findings

- High CSN6 expression in PDAC is linked to poor prognosis and gemcitabine resistance.
- CSN6 stabilizes NPM1 by antagonizing DCAF1-mediated ubiquitination, enhancing ribosome biogenesis.
- Inhibiting the CSN6-NPM1 axis synergizes with gemcitabine to suppress tumor growth in resistant PDAC.

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer with poor prognosis. COP9 signalosome subunit 6 (CSN6), a key regulator of different E3 ubiquitin ligases, plays oncogenic roles in various cancers. However, its function in PDAC remains elusive. Here, this demonstrates that human PDAC tumors expressing high levels of CSN6 present with poor prognosis and gemcitabine resistance. Conditional knockout (KO) of CSN6 hinders tumor formation in a KPP spontaneous PDAC mouse model. Proteomic analysis indicates that CSN6 promotes ribosome biogenesis by activating rDNA transcription and protein synthesis. Mechanistically, CSN6 antagonizes DDB1‐CUL4 associated factor 1 (DCAF1)‐mediated ubiquitination of Nucleophosmin (NPM1), thereby promoting NPM1‐orchestrated ribosome biogenesis. In line with CSN6‐mediated gemcitabine resistance, CSN6‐NPM1 axis enhances ribosome biogenesis, thereby promoting translation of gemcitabine resistance genes, including Cytidine deaminase (CDA), Ribonucleotide reductase subunit M1/2 (RRM1/2). Significantly, combining gemcitabine with NPM1 inhibitor NSC348884 synergistically suppresses CSN6‐high pancreatic cancer xenografts. Clinically, CSN6 expression positively correlates with NPM1 in PDAC tissues, and their concurrent high expression is significantly associated with poor clinical outcomes. This study characterizes CSN6 as an oncogenic protein that promotes NPM1 stabilization by interacting with DCAF1, thereby enhancing ribosome biogenesis and cellular resistance to gemcitabine in PDAC. NPM1 may serve as a therapeutic target for CSN6 high PDAC that exhibits gemcitabine drug resistance.

COP9 signalosome subunit 6 (CSN6) promotes the auto‐ubiquitination and degradation of DDB1‐CUL4 associated factor 1 (DCAF1), thereby antagonizing DCAF1‐mediated ubiquitination of Nucleophosmin (NPM1). This stabilization of NPM1 enhances the ribosome biogenesis process and the translation of specific gemcitabine‐resistance proteins, ultimately driving tumor progression and chemoresistance. Conversely, pharmacological inhibition of the CSN6‐NPM1 axis suppresses tumor growth and alleviates gemcitabine resistance.