Department of Pharmacology, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA.
Division of Medical Oncology, University of Colorado Anschutz Medical Center. Aurora, CO 80045, USA.
Cells. 2019 Sep 20;8(10):1115. doi: 10.3390/cells8101115.
Prostate cancer (PCa) is the most common cancer in men, and the global burden of the disease is rising. The majority of PCa deaths are due to metastasis that are highly resistant to current hormonal treatments; this state is called castration-resistant prostate cancer (CRPC). In this study, we focused on the role of the lipid catabolism enzyme in supporting CRPC growth in an androgen-dependent manner. We found that androgen withdrawal promoted the growth of over-expressing (OE) tumors while it decreased the growth of under-expressing (KD) tumors, increasing their sensitivity to enzalutamide. Mechanistically, we found that OE cells burned more lipid and showed increased histone acetylation changes that were partially reversed with a p300 specific inhibitor. Conversely, KD cells showed less histone acetylation when grown in androgen-deprived conditions. Our results suggest that supports CRPC by supplying acetyl groups for histone acetylation, promoting growth and antiandrogen resistance.
前列腺癌（PCa）是男性中最常见的癌症，全球疾病负担正在上升。大多数 PCa 死亡是由于转移，而转移对当前的激素治疗具有高度耐药性；这种状态称为去势抵抗性前列腺癌（CRPC）。在这项研究中，我们专注于脂质分解酶在以雄激素依赖方式支持 CRPC 生长中的作用。我们发现雄激素剥夺促进了过度表达（OE）肿瘤的生长，而降低了低表达（KD）肿瘤的生长，增加了它们对恩杂鲁胺的敏感性。从机制上讲，我们发现 OE 细胞燃烧更多的脂质，并显示出组蛋白乙酰化变化增加，而用 p300 特异性抑制剂部分逆转了这些变化。相反，在雄激素剥夺条件下生长时，KD 细胞的组蛋白乙酰化减少。我们的结果表明，通过提供组蛋白乙酰化的乙酰基，支持 CRPC 的生长和抗雄激素耐药性。
