CBP Loss Cooperates with PTEN Haploinsufficiency to Drive Prostate Cancer: Implications for Epigenetic Therapy

Abstract

Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−;Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones, in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1 and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic targeted therapy in prostate cancer patients.

LncRNA MALAT1 promotes development of mantle cell lymphoma by associating with EZH2

“…And siRNA-mediated knockdown of EZH2 increased the mRNA expression of CDKN1A/p21 and CDKN1B/p27, leading to cell cycle arrest at G1/S transition in DLBCL and MCL cell lines [24, 43]. Consistently, in several solid tumors (such as prostate cancer, ovarian cancer and lung cancer), CDKN1A/p21 and CDKN1B/p27 were identified as EZH2 targets by ChIP-qPCR analysis, and inhibited due to elevated level of EZH2 [44–47]. …”

PTEN Loss Promotes Intratumoral Androgen Synthesis and Tumor Microenvironment Remodeling via Aberrant Activation of RUNX2 in Castration-Resistant Prostate Cancer

“…Cohorts of Runx2 +/- ; Pten pc-/- , Runx2 +/- and Pten pc-/- mice were generated from PB -Cre + ; Runx2 +/- ; Pten L/L males and Pten L/L females, which were obtained by cross breeding PB-Cre males with Runx2 +/- and Pten L/L females. All procedures were approved by the Mayo Clinic Institutional Animal Care and Use Committee (IACUC) and conform to the legal mandates and federal guidelines for the care and maintenance of laboratory animals in accordance with recommendations as described (16,17). …”

“…Genotyping of wild-type and knockout allele of Runx2 , conditional alleles of Pten , and Cre transgene was performed according to previously described PCR protocols (16,17). Information for primers used is provided in Supplementary Table S1.…”

“…Western blotting was performed as described previously (16,17). Antibodies used for western blotting were diluted at 1:1,000 to 1:2,000.…”

Therapeutic Applications of the Prostate Cancer Epigenome

“…However, several lines of evidence actually support a negative effect of HDACi on AR signaling [96]. To illustrate this point, CBP (KAT3A), which behaves as a bona fide AR coactivator is lost in a proportion of PCa and correlates with PTEN loss [134]. In addition, HDACi (TSA, SAHA, and LBH589) block transcriptional activation of HDAC-dependent AR target genes, predominantly by interfering with the assembly of the RNA polymerase II complex, and also by inhibiting transcription of the AR gene [96,116].…”