Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Genet. 2022 May;54(5):670-683. doi: 10.1038/s41588-022-01045-8. Epub 2022 Apr 25.
HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with early-onset PCa. Independently of AR, HOXB13 recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators such as fatty acid synthase. Analysis of human tissues reveals that the HOXB13 gene is hypermethylated and downregulated in approximately 30% of metastatic castration-resistant PCa. HOXB13 loss or G84E mutation leads to lipid accumulation in PCa cells, thereby promoting cell motility and xenograft tumor metastasis, which is mitigated by pharmaceutical inhibition of fatty acid synthase. In summary, we present evidence that HOXB13 recruits HDAC3 to suppress de novo lipogenesis and inhibit tumor metastasis and that lipogenic pathway inhibitors may be useful to treat HOXB13-low PCa.
HOXB13 是一种同源结构域转录因子，对雄激素受体 (AR) 的活性和雄激素依赖性前列腺癌 (PCa) 的生长具有关键的调控作用。然而，其在 AR 非依赖性环境中的功能仍然难以捉摸。在这里，我们报告 HOXB13 与组蛋白去乙酰化酶 HDAC3 的相互作用，该相互作用被与早发性 PCa 相关的 HOXB13 G84E 突变所破坏。独立于 AR，HOXB13 将 HDAC3 募集到脂肪生成增强子，以催化组蛋白去乙酰化，并抑制脂肪生成调节剂，如脂肪酸合酶。对人类组织的分析表明，HOXB13 基因在大约 30%的转移性去势抵抗性 PCa 中发生超甲基化和下调。HOXB13 的缺失或 G84E 突变导致 PCa 细胞中的脂质积累，从而促进细胞迁移和异种移植肿瘤转移，而脂肪酸合酶的药物抑制可减轻这种作用。总之，我们提供的证据表明，HOXB13 募集 HDAC3 以抑制从头脂肪生成并抑制肿瘤转移，并且脂肪生成途径抑制剂可能对治疗 HOXB13 低表达的 PCa 有用。
