LBPO.TB02 · 肿瘤生物学 · Late-Breaking
靶向p300/CBP消除HOXB13缺失诱导的脂肪生成和肿瘤转移
Targeting p300/CBP abolishes HOXB13 loss-induced lipogenesis and tumor metastasis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：HOXB13是一种前列腺特异性转录因子，最广为人知的是其作为雄激素受体（AR）辅因子的作用。我们此前曾报道，HOXB13在前列腺癌（PCa）中具有一种不依赖AR的功能，即通过招募HDAC3/NCoR抑制脂肪生成程序。这种招募导致H3K27去乙酰化并抑制脂质生物合成。相应地，约30%的转移性CRPC肿瘤中观察到HOXB13缺失。然而，HOXB13缺失与肿瘤转移之间的直接联系仍不清楚。
方法：在HOXB13敲低（KD）、p300/CBP敲低或用p300/CBP抑制剂CCS1477处理的PCa细胞系（LNCaP、PC-3M、22Rv1）中进行了ChIP-seq、RNA-seq和功能测定（脂质染色、细胞侵袭）。免疫组织化学（IHC）分析了56例原发性和56例淋巴结（LN）转移性激素初治PCa样本（Emory队列）以及80例激素治疗PCa样本（NYU队列）中的HOXB13表达。使用经CCS1477处理的静脉注射PC-3M异种移植评估了体内转移。
结果：机制上，我们发现p300/CBP与HOXB13/HDAC3共同占据脂肪生成增强子。HOXB13耗竭增加了H3K27ac并激活了脂肪生成基因，而阻断p300/CBP则抑制了这些变化，表明p300/CBP是HOXB13低表达状态下增强子激活所必需的。转录组分析鉴定出数百个依赖p300/CBP的HOXB13缺失诱导转录本，尤其富集于类固醇和脂肪酸代谢。HOXB13缺失还产生了明显的促转移表型。对临床样本的分析显示，与匹配的原发肿瘤相比，激素敏感患者的淋巴结转移中HOXB13表达降低。功能上，HOXB13缺失增加了脂质积累和侵袭，并伴有脂质响应性MMP的上调，而广谱MMP抑制则减少了侵袭。重要的是，靶向p300/CBP有效阻断了HOXB13下调所引起的一系列变化。同样地，HOXB13敲低在体内增加了转移，而这被CCS1477消除且无明显毒性。
结论：HOXB13缺失破坏了脂肪生成增强子处HOXB13/HDAC3-p300/CBP的平衡，增加了H3K27ac、脂肪生成以及驱动PCa侵袭和转移的脂质响应性MMP。抑制p300/CBP可逆转这些表型，因此可能作为一种针对低HOXB13的转移性激素敏感PCa的有前景的治疗策略。
查看英文原文 English abstract
Background: HOXB13 is a prostate-specific transcription factor best known for its role as an androgen receptor (AR) cofactor. We have previously reported that HOXB13 has an AR-independent function in repressing lipogenic programs via recruitment of HDAC3/NCoR in prostate cancer (PCa). This recruitment leads to deacetylation of H3K27 and suppression of lipid biosynthesis. Accordingly, HOXB13 loss is observed in approximately 30% of metastatic CRPC tumors. However, a direct link between HOXB13 loss and tumor metastasis remains unclear.
Methods: ChIP-seq, RNA-seq, and functional assays (lipid staining, cell invasion) were performed in PCa cell lines (LNCaP, PC-3M, 22Rv1) with HOXB13 knockdown (KD), p300/CBP KD, or treatment with the p300/CBP inhibitor CCS1477. Immunohistochemistry (IHC) analyzed HOXB13 expression in 56 primary and 56 lymph node (LN) metastatic hormone-naive PCa samples (Emory cohort) and 80 hormone-treated PCa samples (NYU cohort). In vivo metastasis was evaluated using intravenous PC-3M xenografts treated with CCS1477.
Results: Mechanistically, we found that p300/CBP co-occupy lipogenic enhancers with HOXB13/HDAC3. HOXB13 depletion increased H3K27ac and activated lipogenic genes, block p300/CBP suppressed these changes, indicating that p300/CBP are required for enhancer activation in the HOXB13-low state. Transcriptome analysis identified hundreds of HOXB13-loss-induced transcripts dependent on p300/CBP, especially enriched for steroid and fatty acid metabolism. Loss of HOXB13 also produced clear pro-metastatic phenotypes. Analysis of clinical samples showed reduced HOXB13 expression in lymph-node metastases from hormone-sensitive patients compared with matched primary tumors. Functionally, HOXB13 loss increased lipid accumulation and invasion, accompanied by upregulation of lipid-responsive MMPs, broad-spectrum MMP inhibition reduced invasion. Importantly, targeting p300/CBP effectively blocked the cascade of changes caused by HOXB13 downregulation. Similarly, HOXB13 knockdown increased metastasis in vivo, which was abolished by CCS1477 without apparent toxicity.
Conclusion: Loss of HOXB13 disrupts the HOXB13/HDAC3-p300/CBP balance at lipogenic enhancers, increasing H3K27ac, lipogenesis, and lipid-responsive MMPs that drive PCa invasion and metastasis. Inhibition of p300/CBP reverses these phenotypes and thus may serve as a promising therapeutic strategy for metastatic hormone-sensitive PCa with low HOXB13.
利益披露 Disclosure
X. Lu, None..
L. Peng, None..
Q. Chu, None..
S. Ye, None..
M. Liu, None..
M. Hussain, None..
M. A. Bilen, None..
L. R. Harik, None..
J. Melamed, None..
J. C. Zhao, None..
J. Yu, None.