攀升性前列腺癌（PCa）向神经内分泌性前列腺癌（NEPC）进展的机制尚不清楚。两个主要的NEPC表型是NE标记物表达升高和血管生成增强。识别联系血管生成和神经内分泌分化（NED）的仍然难以捉摸的直接分子连接是我们理解和针对NEPC的关键。在这里，我们发现组蛋白去乙酰化酶2（HDAC2）在NEPC中的作用尚未报告，但是成为NEPC中最明显上调的表观遗传调节因子之一。HDAC2促进NED和血管生成。G蛋白耦联受体激酶3（GRK3）在NEPC中也有上调表达，是这两个表型的关键促进因子。值得注意的是，GRK3在S394位点磷酸化HDAC2，增强了HDAC2对潜在抗血管生成因子凝血酶抑制素1（TSP1）和NE抑制因子RE1默默转录因子（REST）的表观遗传抑制作用。有趣的是，在前列腺癌细胞中，REST抑制血管生成，而TSP1抑制NE标记物的表达，表明它们的新功能以及它们在相互抑制这两个表型方面的协同作用。此外，GRK3-HDAC2途径在雄激素剥夺疗法和缺氧两种已知促进PCa NED和血管生成的情况下被激活。这些结果表明，NED和血管生成在GRK3增强的HDAC2抑制REST和TSP1上汇合，构成了NEPC两个显著表型之间的关键缺失连接。版权所有。Elsevier B.V.出版。

The mechanisms underlying the progression of prostate cancer (PCa) to neuroendocrine prostate cancer (NEPC), an aggressive PCa variant, are largely unclear. Two prominent NEPC phenotypes are elevated NE marker expression and heightened angiogenesis. Identifying the still elusive direct molecular links connecting angiogenesis and neuroendocrine differentiation (NED) is crucial for our understanding and targeting of NEPC. Here we found that histone deacetylase 2 (HDAC2), whose role in NEPC has not been reported, is one of the most upregulated epigenetic regulators in NEPC. HDAC2 promotes both NED and angiogenesis. G protein-coupled receptor kinase 3 (GRK3), also upregulated in NEPC, is a critical promoter for both phenotypes too. Of note, GRK3 phosphorylates HDAC2 at S394, which enhances HDAC2's epigenetic repression of potent anti-angiogenic factor Thrombospondin 1 (TSP1) and master NE-repressor RE1 Silencing Transcription Factor (REST). Intriguingly, REST suppresses angiogenesis while TSP1 suppresses NE marker expression in PCa cells, indicative of their novel functions and their synergy in cross-repressing the two phenotypes. Furthermore, the GRK3-HDAC2 pathway is activated by androgen deprivation therapy and hypoxia, both known to promote NED and angiogenesis in PCa. These results indicate that NED and angiogenesis converge on GRK3-enhanced HDAC2 suppression of REST and TSP1, which constitutes a key missing link between two prominent phenotypes of NEPC.Copyright © 2023. Published by Elsevier B.V.