小柯机器人

美国西北大学Jindan Yu、Jonathan C. Zhao等研究人员合作发现，HOXB13通过HDAC3介导的表观遗传重编程抑制前列腺癌的从头脂肪生成。相关论文于2022年4月25日在线发表在《自然—遗传学》杂志上。

研究人员表示，HOXB13是一个顺式结构转录因子，对雄性激素受体（AR）的活性和雄性激素依赖性前列腺癌（PCa）的生长起着关键的调节作用。然而，它在不依赖AR的情况下的功能仍然难以捉摸。

研究人员报告了HOXB13与组蛋白去乙酰化酶HDAC3的相互作用，该作用被HOXB13 G84E突变破坏，该突变与早发的PCa有关。不依赖于AR，HOXB13将HDAC3招募到生脂增强子，从而催化组蛋白去乙酰化并抑制生脂调节因子，如脂肪酸合成酶。对人体组织的分析显示，HOXB13基因在大约30%的转移性耐去势PCa中是高甲基化和下调的。HOXB13缺失或G84E突变导致PCa细胞的脂质积累，从而促进细胞运动和异种移植肿瘤的转移，通过药物抑制脂肪酸合成酶可以缓解这种情况。综上所述，研究人员表明，HOXB13招募HDAC3来抑制新的脂肪生成并抑制肿瘤转移，生脂途径抑制剂可能有助于治疗HOXB13低的PCa。

附：英文原文

Title: HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer

Author: Lu, Xiaodong, Fong, Ka-wing, Gritsina, Galina, Wang, Fang, Baca, Sylvan C., Brea, Lourdes T., Berchuck, Jacob E., Spisak, Sandor, Ross, Jenny, Morrissey, Colm, Corey, Eva, Chandel, Navdeep S., Catalona, William J., Yang, Ximing, Freedman, Matthew L., Zhao, Jonathan C., Yu, Jindan

Issue&Volume: 2022-04-25

Abstract: 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 suppresses a lipogenic transcriptional program in prostate cancer (PCa) through HDAC3 recruitment to enhancers. Loss of HOXB13 leads to lipid accumulation in PCa cells, promoting cell motility in vitro and xenograft tumor metastasis in vivo.

DOI: 10.1038/s41588-022-01045-8

Source: https://www.nature.com/articles/s41588-022-01045-8

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