HNRNPUL1 inhibits cisplatin sensitivity of esophageal squamous cell carcinoma through regulating the formation of circMAN1A2

Highlights: • HNRNPUL1 is an independent prognostic factor of ESCC patients receiving platinum-based chemotherapy. • Knockdown of HNRNPUL1 enhances cisplatin sensitivity of ESCC cells. • HNRNPUL1 inhibits the cisplatin sensitivity of ESCC cells by regulating the formation of circMAN1A2. Cisplatin (CDDP) is widely used for chemotherapy of esophageal squamous cell carcinoma (ESCC) but the drug resistance limits its therapeutic benefit. Heterogeneous nuclear ribonucleoprotein U-like 1 (HNRNPUL1) belongs to the family of RNA-binding proteins (RBPs) and is involved in DNA damage repair. To investigate whether and how HNRNPUL1 affects CDDP resistance of ESCC, we evaluated the expression of HNRNPUL1 and found that it was associated with recurrence in ESCC patients receiving postoperative platinum-based chemotherapy and was an independent prognostic factor for disease-free survival (DFS). Besides, we showed that the reduced expression of HNRNPUL1 enhanced the CDDP sensitivity of ESCC cells. Furthermore, RNA immunoprecipitation coupled with high-throughput sequencing (RIP-seq) were performed and a range of HNRNPUL1-binding RNAs influenced by CDDP treatment were identified followed by bioinformatics analysis. In terms of mechanism, we found that HNRNPUL1 inhibited CDDP sensitivity of ESCC cells by regulating the CDDP sensitivity-inhibited circular RNA (circRNA) MAN1A2 formation. Taken together, our results first demonstrated the role of HNRNPUL1 in CDDP resistance of ESCC and suggested that HNRNPUL1 may be a potential target of ESCC chemotherapy.