PRPF40A coordinates RNA splicing and A-to-I editing to drive/control pancreatic tumor progression and chemoresistance
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with limited therapeutic options and poor prognosis. In this study, we identify the splicing factor PRPF40A as a key regulator of PDAC progression through its coordinated control of alternative splicing and adenosine-to-inosine (A-to-I) RNA editing. PRPF40A is markedly overexpressed in PDAC cells, and its silencing selectively impairs cancer cell proliferation, induces cell-cycle modulation and apoptosis, and disrupts migratory and survival mechanisms, including anoikis resistance. Transcriptomic profiling reveals that PRPF40A depletion disrupts splicing and transcriptional programs and alters ADAR-mediated RNA editing activity, reducing functional editing at specific coding sites while increasing global editing across repetitive elements. Importantly, in vivo PRPF40A silencing significantly suppresses pancreatic tumor growth, and PRPF40A depletion enhances gemcitabine-induced apoptosis across multiple PDAC models, revealing a potent chemosensitizing effect. Together, these findings uncover a previously unrecognized RNA-processing axis essential for PDAC malignancy and highlight PRPF40A as a promising therapeutic target whose inhibition may improve treatment response and limit tumor progression.