Background:The role of the lysine acetyltransferase GCN5 in cancer development remains largely unknown. Results: GCN5 expression correlates with lung cancer tumor size, directly enhances the expression of E2F1, cyclin E1, and cyclin D1, and potentiates lung cancer growth. Conclusion: GCN5 potentiates lung cancer growth in an E2F1-dependent manner. Significance: GCN5 is critical for lung cancer growth and represents a potential target for the treatment of lung cancer.

Sirt2, a member of the NAD+-dependent protein deacetylase family, is increasingly recognized as a critical regulator of the cell cycle, cellular necrosis and cytoskeleton organization. However, its role in embryonic stem cells (ESCs) remains unclear. Here we demonstrate that Sirt2 is up-regulated during RA (retinoic acid)-induced and embryoid body (EB) differentiation of mouse ESCs. Using lentivirus-mediated shRNA methods, we found that knockdown of Sirt2 compromises the differentiation of mouse ESCs into ectoderm while promoting mesoderm and endoderm differentiation. Knockdown of Sirt2 expression also leads to the activation of GSK3β through decreased phosphorylation of the serine at position 9 (Ser9) but not tyrosine at position 216 (Tyr216). Moreover, the constitutive activation of GSK3β during EB differentiation mimics the effect of Sirt2 knockdown, while down-regulation of GSK3β rescues the effect of Sirt2 knockdown on differentiation. In contrast to the effect on lineage differentiation, Sirt2 knockdown and GSK3β up-regulation do not change the self-renewal state of mouse ESCs. Overall, our report reveals a new function for Sirt2 in regulating the proper lineage commitment of mouse ESCs.

In mammalian germ cells, meiotic commitment requires the expression of Stimulated by retinoic acid gene 8 (Stra8), which is transcriptionally activated by retinoic acid (RA). However, little is known about the epigenetic mechanism by which RA induces Stra8 expression. Utilizing a chromatin immunoprecipitation assay (ChIP), we showed that RA increases histone acetylation at the Stra8 promoter in murine embryonic stem cells (ESCs), a model for germ cell differentiation. Furthermore, we explored whether two coregulators with histone acetyltransferase (HAT) activity, Creb-binding protein (CBP) and p300, are involved in the activation of Stra8. The lentiviral shRNA knockdown of endogenous CBP led to Stra8 repression, while the overexpression of CBP enhanced Stra8 expression at both the mRNA and protein levels. ChIP analysis confirmed that CBP is the crucial coactivator for RA-mediated Stra8 transcription and that it enhances the level of histone acetylation and recruits RNA polymerase II to establish transcriptionally active chromatin. Furthermore, shRNA of p300 enhanced Stra8 expression, and the overexpression of p300 reduced Stra8 expression, independently of its HAT activity. ChIP showed that the knockdown of p300 significantly increased the level of CBP at the Stra8 promoter. These findings demonstrate that CBP and p300 play distinct roles in RA-mediated Stra8 gene transcription.