Restoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP-PML axis in prostate cancer (PC). We show that knockdown (KD) of E6AP expression attenuates growth of PC cell lines in vitro. We validated this finding in vivo using cell line xenografts, patient-derived xenografts and mouse genetics. We found that KD of E6AP attenuates cancer cell growth by promoting cellular senescence in vivo, which correlates with restoration of tumor suppression by PML. In addition, we show that KD of E6AP sensitizes cells to radiation-induced death. Overall, our findings demonstrate a role for E6AP in the promotion of PC and support E6AP targeting as a novel approach for PC treatment, either alone or in combination with radiation.

The microRNAs and microRNA clusters have been implicated in normal cardiac development and also disease, including cardiac hypertrophy, cardiomyopathy, heart failure, and arrhythmias. Since a microRNA cluster has from two to dozens of microRNAs, the expression of a microRNA cluster could have a substantial impact on its target genes. In the present study, the configuration and distribution of microRNA clusters in the mouse genome were examined at various inter-microRNA distances. Three important microRNA clusters that are significantly impacted during adult cardiac aging, the miR-17-92, miR-106a-363, and miR-106b-25, were also examined in terms of their genomic location, RNA transcript character, sequence homology, and their relationship with the corresponding microRNA families. Multiple microRNAs derived from the three clusters potentially target various protein components of the cdc42-SRF signaling pathway, which regulates cytoskeleton dynamics associated with cardiac structure and function. The data indicate that aging impacted the expression of both guide and passenger strands of the microRNA clusters; nutrient stress also affected the expression of the three microRNA clusters. The miR-17-92, miR-106a-363, and miR-106b-25 clusters are likely to impact the Cdc42-SRF signaling pathway and thereby affect cardiac morphology and function during pathological conditions and the aging process.

p49/STRAP (SRFBP1) is a transcriptional regulator that has been implicated in cardiac aging. p49/STRAP has a SRF binding domain and a BUD22 domain (which modulates cellular growth rate and cell size). We have observed that p49/STRAP alters the intracellular NAD/NADH ratio and induces protein deacetylation. Here we report that p49/STRAP overexpression caused the deacetylation of histone H4 on lysine 16 (H4K16) and suppressed the expression of PGC-1α as well as mitofusin-1 and mitofusin-2 at both the mRNA and protein levels. P49/STRAP also reduced mitochondrial size, mitochondrial membrane potential and the mitochondrial oxygen consumption rate. We noted that P49/STRAP expression was increased in the old versus young adult mouse hearts and also increased with advancing population doubling levels in cultured human umbilical vein endothelial cells (HUVECs). It is therefore very plausible that increased expression of p49/STRAP in late life may alter the status of histone acetylation and impact mitochondrial dynamics and thereby reduce mitochondrial function and cardiac performance during mammalian senescence.