HDAC1 overexpression enhances β-cell proliferation by down-regulating Cdkn1b/p27

The homeobox transcription factor Nkx6.1 is sufficient to increase functional beta-cell mass, where functional beta-cell mass refers to the combination of beta-cell proliferation, glucose-stimulated insulin secretion (GSIS) and beta-cell survival. Here, we demonstrate that the histone deacetylase 1 (HDAC1), which is an early target of Nkx6.1, is sufficient to increase functional beta-cell mass. We show that HDAC activity is necessary for Nkx6.1-mediated proliferation, and that HDAC1 is sufficient to increase beta-cell proliferation in primary rat islets and the INS-1 832/13 beta-cell line. The increase in HDAC1-mediated proliferation occurs while maintaining GSIS and increasing beta-cell survival in response to apoptotic stimuli. We demonstrate that HDAC1 overexpression results in decreased expression of the cell cycle inhibitor Cdkn1b/p27 which is essential for inhibiting the G1 to S phase transition of the cell cycle. This corresponds with increased expression of key cell cycle activators, such as Cyclin A2, Cyclin B1 and E2F1, which are activated by activation of the Cdk4/Cdk6/Cyclin D holoenzymes due to down-regulation of Cdkn1b/p27. Finally, we demonstrate that overexpression of Cdkn1b/p27 inhibits HDAC1-mediated beta-cell proliferation. Our data suggest that HDAC1 is critical for the Nkx6.1-mediated pathway that enhances functional beta-cell mass.