# DDX21 Controls Cell Cycle Progression and Autophagy in Pancreatic Cancer Cells

## TL;DR

This study shows that the RNA helicase DDX21 promotes cancer growth in pancreatic cancer by regulating cell cycle and autophagy, suggesting it as a potential therapeutic target.

## Contribution

The study reveals a new role for DDX21 in regulating autophagy and cell cycle progression in pancreatic cancer cells.

## Key findings

- DDX21 is upregulated in liver metastasis of pancreatic cancer patients.
- Depletion of DDX21 increases autophagy and disrupts cell cycle progression in PDAC cells.
- DDX21 inactivation reduces PDAC cell proliferation and clonogenic activity.

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease, with a 5-year survival rate < 10%. Current therapies are poorly effective, thus urging the identification of new therapeutic approaches to face this lethal cancer. The RNA helicase DDX21 was recently shown to be upregulated and to associate with poor prognosis in PDAC. Our study shows that DDX21 is further upregulated in liver metastasis with respect to the primary PDAC lesions, and that depletion of DDX21 triggers autophagy while perturbing the cell cycle progression of PDAC. Together, our data support the oncogenic function of DDX21 in PDAC cells and uncover biological processes and pathways modulated by this RNA helicase.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer. Late diagnosis and acquisition of chemoresistance contribute to its dismal prognosis. While surgical resection improved the clinical outcome of patients, only ~20% of them are eligible due to advanced disease at diagnosis. Thus, the development of new therapeutic approaches is a master priority for an improved management of this cancer. The helicase DDX21 was proposed as a prognostic marker in several tumors, including PDAC. Methods: DDX21 expression was evaluated in PDAC samples and cell lines; RNA sequencing and bioinformatics analyses of DDX21-depleted PANC-1 silenced cells; functional analyses of autophagy, cell cycle and proliferation. Results: DDX21 is expressed at higher levels in liver metastasis of PDAC patients. Transcriptomics analyses of DDX21-depleted cells revealed an enrichment in genes involved in autophagy and cell cycle progression. The inactivation of DDX21 by RNA interference enhanced the basal autophagic flux and altered the cell cycle by reducing the rate of G1-S transition. Coherently, PDAC cell proliferation and clonogenic activity was significantly reduced. Conclusions: Our results support the oncogenic role of DDX21 in PDAC and uncover a new role for this helicase in the regulation of basal autophagy.