Phosphodiesterase 5 Signals through HIPPO/TAZ Pathway in Maintaining Stemness of Prostate Cancer Cells

Abstract

Cancer stemness is critical for the metastasis and relapse, however, the mechanism governing the maintenance of cancer stemness remains unknown. Herein, we have investigated the roles of phosphodiesterase 5 (PDE5) in stemness of prostate cancer cells. Both PDE5 and WW domain-containing transcription regulator protein 1 (TAZ), a major co-effector of the Hippo tumor suppressor pathway, are highly expressed in the PC3-derived cancer stem cells (PCSCs), and contribute to maintaining the stemness of PCSCs. Moreover, inhibition of PDE5 activity activates cGMP-dependent protein kinase G (PKG), PKG in turn activates MST/Lats kinases, leads to the cytosolic instability, and attenuates nucleus translocation of TAZ, resulting in inactivation of Hippo signaling. PDE5 inhibitor, vardenafil, not only attenuates the stemness of PCSCs but induces the trans-differentiation of them, these effects are abolished by knockdown of TAZ expression in PCSCs. Finally, in PC3 cells- and PCSCs-derived xenografts, administration of PDE5 inhibitor to the nude mice reverses the stem markers expression, whereas knockdown of TAZ in PC3 cells and PCSCs leads to the decreases in tumorigenesis and elimination of PDE5 inhibitors’ effects. Collectively, the present study demonstrates that inhibition of PDE5 activates hippo signaling to suppress TAZ in maintaining the stemness of PCSCs, and that PDE5 inhibitors could be an effective therapeutic intervention for metastasis and relapse of prostate cancer.