TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis.
TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis.
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DOI：
10.1158/0008-5472.can-16-2797
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发表时间：
2017-06-15
期刊：
影响因子：
11.2
通讯作者：
Tran PT
中科院分区：
文献类型：
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作者：
Malek R;Gajula RP;Williams RD;Nghiem B;Simons BW;Nugent K;Wang H;Taparra K;Lemtiri-Chlieh G;Yoon AR;True L;An SS;DeWeese TL;Ross AE;Schaeffer EM;Pienta KJ;Hurley PJ;Morrissey C;Tran PT
TWIST1 是一种对发育至关重要的转录因子，可促进前列腺癌转移。在胚胎发育过程中，TWIST1 和 HOXA9 在小鼠前列腺中共表达，然后在出生后沉默。在这里，我们报告说，TWIST1 和 HOXA9 共表达在小鼠和人类原发性前列腺肿瘤中重新激活，并在人类转移瘤中进一步富集，与生存相关。 TWIST1 与 WDR5 和 lncRNA Hottip/HOTTIP 形成复合物，它们是 MLL/COMPASS 样 H3K4 甲基化酶的成员，在发育过程中调节 Hox/HOX 簇中的染色质。 TWIST1 过表达导致 TWIST1 和 WDR5 共富集，并增加依赖于 WDR5 的 Hoxa9/HOXA9 启动子处的 H3K4me3 染色质。 WDR5 和 Hottip/HOTTIP 的表达也是 TWIST1 诱导的 HOXA9 上调和侵袭性细胞表型（例如侵袭和迁移）所必需的。 HOXA9 的药理学抑制可防止 TWIST1 诱导的体外侵袭性前列腺癌细胞表型和体内转移。这项研究展示了一种新机制，TWIST1 通过与 COMPASS 样复合物合作来增加靶基因启动子处的 H3K4 三甲基化，从而调节染色质和基因表达。我们的研究结果强调了 TWIST1-HOXA9 胚胎前列腺发育程序，该程序在前列腺癌转移过程中重新激活，并且具有治疗靶向性。
TWIST1 is a transcription factor critical for development which can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are co-expressed in mouse prostate and then silenced post-natally. Here we report that TWIST1 and HOXA9 co-expression are re-activated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS-like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development. TWIST1 overexpression led to co-enrichment of TWIST1 and WDR5 as well increased H3K4me3 chromatin at the Hoxa9/HOXA9 promoter which was dependent on WDR5. Expression of WDR5 and Hottip/HOTTIP was also required for TWIST1-induced upregulation of HOXA9 and aggressive cellular phenotypes such as invasion and migration. Pharmacological inhibition of HOXA9 prevented TWIST1-induced aggressive prostate cancer cellular phenotypes in vitro and metastasis in vivo. This study demonstrates a novel mechanism by which TWIST1 regulates chromatin and gene expression by cooperating with the COMPASS-like complex to increase H3K4 trimethylation at target gene promoters. Our findings highlight a TWIST1-HOXA9 embryonic prostate developmental program that is reactivated during prostate cancer metastasis and is therapeutically targetable.