# CERKL Reduced PI3P/Autophagy to Promote Pancreatic Cancer

## TL;DR

This study shows that CERKL promotes pancreatic cancer by reducing autophagy and that a specific mutation enhances its tumor-promoting effects.

## Contribution

The novel finding is the role of CERKL and its L296V mutation in promoting pancreatic cancer via the TRIM21/CERKL/autophagy pathway.

## Key findings

- CERKL expression is increased in pancreatic cancer and promotes cell migration and invasion.
- The L296V mutation in CERKL enhances its tumor-promoting effects.
- CERKL reduces PI3P and autophagy, and this effect is stronger with the L296V mutation.

## Abstract

Pancreatic cancer (PC) is one of the common malignant tumors in gastrointestinal tract. The roles of CERKL in PC are unknown.

Here, online databases were used to analyze CERKL mRNA expression and mutation in PC, predict E3 ligase for CERKL. The roles of CERKL were investigated in cells, mice, and clinic samples. The regulations on CERKL by E3 and lipids fluctuations induced by CERKL were analyzed.

It was found that the expression levels of CERKL mRNA and protein were significantly increased in PC. Meanwhile, CERKL promoted PC cells migration and invasion in vitro and in vivo. L296V mutation on CERKL in PC patient was found in cosmic database. Compared with CERKL, CERKL‐L296V could further promote PC cells migration and invasion. Bioinformatics analysis revealed the negative correlation between E3 TRIM21 and CERKL. Furthermore, Trim21 was validated to negatively regulate and bind to CERKL protein. L296V mutation reduced the interaction between CERKL and Trim21, and the ubiquitination on CERKL. Lipidomic analysis showed CERKL down‐regulation could increase phosphatidylinositol amount in PC cells. Phosphatidylinositol addition reversed the effects of CERKL in PC cells. Moreover, CERKL knocked down increased phosphatidylinositol 3‐phosphate (PI3P) content and autophagy. When CERKL was overexpressed, PI3P and autophagy had opposite changes. Of note, CERKL‐L296V had a stronger effect than CERKL on PI3P and autophagy. CERKL induced metastasis could be reduced by autophagy inducer. Thus, CERKL promoted the migration and invasion of pancreatic cancer. L296V mutation enhances the tumor‐promoting effect of CERKL.

TRIM21/CERKL/autophagy pathway exists in PC.