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NSD2 是 AR/FOXA1 新增强子联合体促进前列腺肿瘤发生的必要亚基。

NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis.

机构信息

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

出版信息

Nat Genet. 2024 Oct;56(10):2132-2143. doi: 10.1038/s41588-024-01893-6. Epub 2024 Sep 9.

DOI:10.1038/s41588-024-01893-6
PMID:39251788
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11525188/
Abstract

Androgen receptor (AR) is a ligand-responsive transcription factor that drives terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to activate malignant phenotypes, the molecular mechanisms of which remain unknown. Here, we show that tumor-specific AR enhancers are critically reliant on H3K36 dimethyltransferase activity of NSD2. NSD2 expression is abnormally induced in prostate cancer, where its inactivation impairs AR transactivation potential by disrupting over 65% of its cistrome. NSD2-dependent AR sites distinctively harbor the chimeric FOXA1:AR half-motif, which exclusively comprise tumor-specific AR enhancer circuitries defined from patient specimens. NSD2 inactivation also engenders increased dependency on the NSD1 paralog, and a dual NSD1/2 PROTAC degrader is preferentially cytotoxic in AR-dependent prostate cancer models. Altogether, we characterize NSD2 as an essential AR neo-enhanceosome subunit that enables its oncogenic activity, and position NSD1/2 as viable co-targets in advanced prostate cancer.

摘要

雄激素受体 (AR) 是一种配体反应性转录因子，可驱动前列腺腔上皮的终末分化。相比之下，在源自这些细胞的肿瘤中，AR 染色质占据被广泛重新编程以激活恶性表型，但其分子机制尚不清楚。在这里，我们表明，肿瘤特异性 AR 增强子严重依赖于 NSD2 的 H3K36 二甲基转移酶活性。NSD2 在前列腺癌中异常表达，其失活通过破坏超过 65%的顺式作用元件来破坏 AR 转录激活潜力。NSD2 依赖性 AR 位点独特地含有嵌合的 FOXA1:AR 半基序，该基序仅包含来自患者标本定义的肿瘤特异性 AR 增强子回路。NSD2 失活还会导致对 NSD1 同源物的依赖性增加，并且 AR 依赖性前列腺癌模型中双重 NSD1/2 PROTAC 降解剂具有更好的细胞毒性。总之，我们将 NSD2 表征为一种必需的 AR 新增强子亚基，使其具有致癌活性，并将 NSD1/2 定位为晚期前列腺癌的可行共同靶标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7797/11525188/a32465805dea/41588_2024_1893_Fig15_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7797/11525188/3cdad24b7324/41588_2024_1893_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7797/11525188/caee448f9f83/41588_2024_1893_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7797/11525188/199c7225fd6f/41588_2024_1893_Fig9_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7797/11525188/5e1c1d9d0713/41588_2024_1893_Fig12_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7797/11525188/76fe816803f2/41588_2024_1893_Fig13_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7797/11525188/1d6c5bd83382/41588_2024_1893_Fig14_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7797/11525188/a32465805dea/41588_2024_1893_Fig15_ESM.jpg

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