MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues [ChIP-seq]
The MYC transcription factor requires MAX for DNA binding and widespread activation of gene expression in both normal and neoplastic cells. Surprisingly, 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 Max inactivation alone produces pituitary adenomas while Max inactivation loss 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 striking 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. Overall design: Mice were generated with conditional mutations in Rb/p53, and Max/Rb/p53 in neuroendocrine cells by crossing into a tamoxifen inducible Ascl-CRE background. Thyroid and pituitary tumors were observed in these mice, and this was accelerated by Max deficiency. Tumors and cell lines from these mice were then profiled by RNA-Seq. We also performed ChIP-Seq for MAX and members of the extended MYC/MAX network (MNT, MLX, MLXIP) to determine how MAX loss changes occupation of the extended MYC network, and how these changes are associated with altered transcription in cancers that develop as a consequence of Max mutation. RP cells are Rb/p53 deficient, and RPMax are Rb/p53/Max deficient