Menin, Histone H3 Methyltransferases, and Regulation of Cell Proliferation: Current Knowledge and Perspective

Menin is a tumor suppressor encoded by the MEN1 gene that is mutated in patients with an inherited syndrome, multiple endocrine neoplasia type 1 (MEN1). Loss of menin has potent impact on proliferation of endocrine and non-endocrine cells. However, until recently little has been known as to how menin regulates cell proliferation. Rapid research progress in the past several years suggests that menin represses proliferation of endocrine cells yet promotes proliferation in certain types of leukemia cells via interacting with various transcriptional regulators. Menin interacts with histone H3 methyltransferases such as MLL (mixed lineage leukemia) protein. Increasing evidence has linked the biological function of menin to epigenetic histone modifications, control of the pattern of gene expression, and regulation of cell proliferation in a cell type-specific manner. In light of these recent findings, an emerging model suggests that menin is a crucial regulator of histone modifiers by acting as a scaffold protein to coordinate gene transcription and cell proliferation in a cell contextdependent manner. This recent progress unravels the coordinating role of menin in epigenetics and regulation of cell cycle, providing novel insights into understanding regulation of beta cell functions and diabetes, as well as the development and therapy of endocrine tumors and leukemia.