YY1 relieves p300 autoinhibition to promote histone acetylation in advanced prostate cancer, enhancing the oncogenic signaling of Androgen Receptor Splice Variant 7

Abstract

Genetic and epigenetic aberrations often act in concert to establish oncogenic transcriptomic programs in aggressive cancers. For example, the development of castration-resistant prostate cancer (CRPC), an advanced prostate cancer form, is closely associated with over-expression and/or hyper-activation of transcription factors (TFs) such as Androgen Receptor (AR) and Yin Yang 1 (YY1), as well as p300, a prominent histone acetyltransferase. How exactly these cancer-related lesions are coordinated to generate a malignant cell state remains elusive. Here, we demonstrate that YY1, which is frequently over-expressed in advanced prostate cancers, allosterically stimulates the acetyltransferase activity of p300 in cis, leading to the globally elevated acetylation of histone H3 lysine 18 and 27 (H3K18ac and H3K27ac). Mechanistically, YY1s N-terminal activation domain (AD) directly interacts with p300s TAZ2 domain, relieving the autoinhibition of p300 to facilitate substrate acetylation. Our integrated genome-wide mapping and transcriptomic studies reveal significant co-localization of genomic binding sites of YY1, androgen receptor splice variant 7 (AR-V7, a constitutively active form of AR) and p300 in CRPC cells, where the YY1-mediated p300 activation and resultant histone acetylation increases promote the oncogenic gene-expression programs downstream of YY1 and AR/AR-V7. Both in vitro and in vivo functional assays demonstrate a critical requirement of the above signaling for the advanced disease progression and drug resistance seen in CRPC. Altogether, this study uncovers that YY1 acts to alleviate p300s autoinhibition at target genes co-bound by oncogenic TFs (YY1 and/or AR/AR-V7) in CRPC, thereby sustaining tumorigenicity. Additionally, the blockade of YY1-mediated gene activation resensitizes CRPC to treatment to the clinic anti-AR agent (enzalutamide), which provides a rationale for overcoming the therapeutic resistance often seen in advanced prostate cancers.