Work

TULP4 degrades RYBP to enhance DNA damage repair and chemosensitivity of pancreatic ductal adenocarcinoma

Year: 2024

Type: article

Abstract: Gemcitabine (GEM) has been extensively used for the treatment of pancreatic ductal adenocarcinoma (PDAC), however, frequently occurred chemoresistance remains a great barrier to achieve long-term disease-free survival for the PDAC patients. We establish a GEM-resistant PDAC cell line and screen key regulators for GEM-resistance using a CRISPR/cas9 sgRNA library targeting 791 human epigenome-related genes, and find that TUB Like Protein 4 (TULP4) is a GEM resistance-associated gene. Clinically,TULP4 is highly expressed in pancreatic cancer among common solid tumors, and upregulated TULP4 is correlated with poor response and disease progression in PDAC patients treated with GEM-based regimens, as well as with a worse overall survival rate. Gain- and loss-of-functions of TULP4 in PDAC cells alter the sensitivity to GEM treatment in vitro, as evidenced by accordingly changed IC50 and cell apoptosis. Gene set enrichment analysis of RNA sequencing for TULP4-depeltion PDAC cells indicates that DNA damage repair process is the main target, and mechanistic analysis reveals that TULP4 interacts with RING1 and YY1 Binding Protein(RYBP), interferences K11- and K48-ubiquitin linked ubiquitination and stabilizes RYBP protein, consequentially enhances DNA repair capacity and engenders GEM resistance in PDAC cells. In addition,TULP4 knockdown inhibits tumor growth and improves GEM sensitivity in a mouse xenograft model of pancreatic cancer in vivo. Thus, our findings reveal a critical role of TULP4 in regulating PDAC chemoresistance, and shed light on developing new strategies to overcome GEM resistance of pancreatic cancer.

Source: Genes & Diseases

DOI: 10.1016/j.gendis.2024.101288