MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues
Menée à l'aide de lignées cellulaires et de modèles murins, cette étude met en évidence un mécanisme par lequel une délétion au niveau du gène MAX, en dérégulant la transcription de MYC et d'autres gènes (MNT, MLX, MondoA), favorise le développement de néoplasies endocrines au niveau de différents tissus
The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Inactivating mutations in MAX are associated with a subset of neuroendocrine cancers including pheochromocytoma, pituitary adenoma, and small cell lung cancer. Neither the extent nor the mechanisms of MAX tumor suppression are well understood. Deleting Max across multiple mouse neuroendocrine tissues, we find that Max inactivation alone produces pituitary adenomas, while Max inactivation cooperates with Rb1/Trp53 loss to accelerate medullary thyroid C cell and pituitary adenoma development. In the thyroid tumor cell lines, MAX loss triggers a marked shift in genomic occupancy by other members of the MYC network (MNT, MLX, MondoA) supporting metabolism, survival, and proliferation of neoplastic neuroendocrine cells. Our work reveals MAX as a broad suppressor of neuroendocrine tumorigenesis through its ability to maintain a balance of genomic occupancies among the diverse transcription factors in the MYC network. MAX inactivation deregulates multiple transcription factors to induce neuroendocrine cancers.
Science Advances , article en libre accès 2025