Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer

Lysosome-mediated autophagy (including mitophagy) is crucial for cell survival and homeostasis. Although the mechanisms of lysosome activation during stress are well recognized, the epigenetic regulation of lysosomal gene expression remains largely unexplored. Menin, encoded by the MEN1 gene, is a chromatin-related protein that is widely involved in gene transcription via histone modifications. Here, we report that menin regulates the transcription of important lysosomal genes through MLL-mediated H3K4me3 reprogramming, which is necessary for maintaining lysosomal homeostasis. Menin also directly controls the expression of SQSTM1 and MAP1LC3B to maintain autophagic flux in an AMPK/mTORC1-independent manner. Moreover, menin maintains mitochondrial genome integrity and homeostasis by tightly regulating TFAM expression. In genetically engineered mouse models, Men1 deficiency resulted in severe lysosomal/mitochondrial dysfunction and an impaired self-clearance ability, which further led to metabolite accumulation and spontaneous lung cancer development. SP2509, a histone demethylase inhibitor, effectively reversed the downregulation of lysosomal/mitochondrial genes caused by loss of Men1. Our study confirms the previously unrecognized biological and mechanistic importance of menin-mediated H3K4me3 in maintaining organelle homeostasis.