MACC1 enhances an oncogenic RNA splicing of IRAK1 through interacting with HNRNPH1 in lung adenocarcinoma

Abstract Dysregulation of alternative pre‐mRNA splicing plays a critical role in the progression of cancers, yet the underlying molecular mechanisms remain largely unknown. It is reported that metastasis‐associated in colon cancer 1 (MACC1) is a novel prognostic and predictive marker in many types of cancers, including lung adenocarcinoma. Here, we reveal that the oncogene MACC1 specifically drives the progression of lung adenocarcinoma through its control over cancer‐related splicing events. MACC1 depletion inhibits lung adenocarcinoma progression through triggering IRAK1 from its long isoform, IRAK1‐L, to the shorter isoform, IRAK1‐S. Mechanistically, MACC1 interacts with splicing factor HNRNPH1 to prevent the production of the short isoform of IRAK1 mRNA. Specifically, the interaction between MACC1 and HNRNPH1 relies on the involvement of MACC1's SH3 domain and HNRNPH1's GYR domain. Further, HNRNPH1 can interact with the pre‐mRNA segment (comprising exon 11) of IRAK1, thereby bridging MACC1's regulation of IRAK1 splicing. Our research not only sheds light on the abnormal splicing regulation in cancer but also uncovers a hitherto unknown function of MACC1 in tumor progression, thereby presenting a novel potential therapeutic target for clinical treatment.