Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor Through cMYC Repression and Recruitment of the DREAM Complex [ChIP-seq]
The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. Targeting the AR has a remarkable therapeutic index and represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer. Though most approaches directed toward the AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA), results in growth repression and improved out-comes in subsets of prostate cancer patients. However, the mechanism(s) contributing to SPA re-sponse and resistance remain unclear. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses determined that the Dimerization partner, RB-like, E2F and Multi-vulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpres-sion of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repres-sion of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM-SIN3A-HDAC complex. As RB1 and DREAM complex stability are regulated by MYC, a key determinant of tumor sensitivity to SPA, treatment may hinge on effectively repress-ing MYC activity. The integrity of MYC signaling and DREAM complex assembly may conse-quently serve as determinants of SPA responses and as pathways mediating SPA resistance. Overall design: This data series contains LNCaP and isogenic TP53/RB1 LNCaP knockout cells lines treated with high-dose R1881. ChIP-seq was performed for E2F1, LIN37, or LIN9. E2F1 ChIP-seq was perfromed in triplicate. LIN37 and LIN9 are single samples. These factors control expression of E2F target genes that are repressed as a result of androgen receptor activity. Input samples were used with MACS2. IgG files are availble as negative controls.