In summary, the results in our study illuminate that: (1) CREB activation enhances EZH2’s PRC2 activity; (2) ADT activates the CREB/EZH2 axis to promote NED and angiogenesis; (3) NED links to angiogenesis and tumor progression in prostate cancer cells through EZH2-mediated epigenetic repression of TSP1; (4) This pathway is activated by castration in prostate tumor xenografts, which is reversed by repression of CREB signaling; (5) The components on this pathway are accordantly expressed in cancer patient samples. Here, CREB1 is linked to prostate cancer.