MEN1 Promotes Ferroptosis by Disrupting CD44 Alternative Splicing to Suppress Lung Cancer

Ferroptosis is a characteristic form of cell death triggered by excessive iron-dependent Reactive Oxygen Species (ROS) that plays an important role in suppressing tumor development. Here, we identified MEN1 as a driver of Ferroptosis in lung Cancer. MEN1 facilitated lipid ROS generation and sensitized lung Cancer cells to Ferroptosis by perturbing CD44 precursor messenger RNA (pre-mRNA) splicing. CD44 variant isoforms were highly expressed and correlated with poor prognosis in human lung cancers. Loss of Men1 profoundly accelerated the progression of mutant Kras driven lung adenocarcinoma (LUAD) and promoted the accumulation of CD44 variant isoforms. Mechanistically, MEN1 maintained a relatively slow RNA polymerase II (Pol II) elongation by controlling the release of PAF1 from the CD44 pre-mRNA, which in turn prevented the inclusion of CD44 variable exons (CD44v). Furthermore, CD44v6-interfering peptides effectively abrogated the growth and metastasis of established MEN1 deficient tumors by activating Ferroptosis. Collectively, this study unveils a mechanism of tumor suppression based on MEN1 regulation of CD44 alternative splicing, ROS production, and Ferroptosis induction.