We examined whether class IIa histone deacetylases (HDACs) play a role in mitogenic signaling mediated by protein kinase D1 (PKD1) in IEC-18 intestinal epithelial cells. Our results show that class IIa HDAC 4, 5 and 7 are prominently expressed in these cells. Simulation with angiotensin II (ANG II), a potent mitogen for IEC-18 cells, induced a striking increase in the phosphorylation of HDAC4 at Ser²⁴⁶ and Ser⁶³², HDAC5 at Ser²⁵⁹ and Ser⁴⁹⁸ and HDAC7 at Ser¹⁵⁵. Treatment with the PKD family inhibitors kb NB 142-70 and CRT0066101 or siRNA-mediated knockdown of PKD1 prevented ANG II-induced phosphorylation of HDAC 4, 5 and 7. A variety of PKD1 activators in IEC-18 cells, including vasopressin, lysophosphatidic acid or phorbol esters, also induced HDAC4, 5 and 7 phosphorylation. Using endogenously and ectopically expressed HDAC5, we show that PKD1-mediated phosphorylation of HDAC5 induces its nuclear extrusion into the cytoplasm. In contrast, HDAC5 with Ser²⁵⁹ and Ser⁴⁹⁸ mutated to Ala was localized to the nucleus in both unstimulated and stimulated cells. Treatment of IEC-18 cells with specific inhibitors of class IIa HDACs, including MC1568 and TMP269, prevented cell cycle progression, DNA synthesis and proliferation induced in response to GPCR/PKD1 activation. The PKD1/class IIa HDAC axis also functions in intestinal epithelial cell in vivo, since an increase in the phosphorylation of HDAC4/5 and HDAC7 was demonstrated in lysates of cryptal cells from PKD1 transgenic mice as compared with matched non-transgenic littermates. Collectively, our results reveal a PKD1/classIIa HDAC axis in intestinal epithelial cells leading to mitogenic signaling.