Alioui Anthony, Dufour Julie, Leoni Valerio, Loregger Anke, Moeton Martina, Iuliano Luigi, Zerbinati Chiara, Septier Amandine, Val Pierre, Fouache Allan, Russo Vincenzo, Volle David H, Lobaccaro Jean-Marc A, Zelcer Noam, Baron Silvère
Université Clermont Auvergne, Génétique Reproduction et Développement, BP 38, F-63001, Clermont-Ferrand, France.
CNRS, UMR 6293, Génétique Reproduction et Développement, F-63001, Clermont-Ferrand, France.
Nat Commun. 2017 Sep 5;8(1):445. doi: 10.1038/s41467-017-00508-5.
Advanced prostate cancer (PCa) is a clinical challenge as no curative therapeutic is available. In this context, a better understanding of metastasis and resistance mechanisms in PCa is an important issue. As phosphatase and tensin homolog (PTEN) loss is the most common genetic lesion in such cancer, we investigate human data sets for mechanisms that can constrain cancer evolution in this setting. Here we report a liver X receptor (LXR) signature, which tightly correlates with PTEN loss, in PCa. Accordingly, the LXR pathway is deregulated in prostate carcinomas in Pten-null mice. Genetic ablation of LXRs in Pten-null mice, exacerbates PCa invasiveness and metastatic dissemination, which involves mesenchymal transition and accumulation of matrix metalloproteinases. Mechanistically, PTEN deletion governed LXR transcriptional activity through deregulation of cholesterol de novo synthesis, resulting in accumulation of endogenous LXR ligands. Our study therefore reveals a functional circuit linking PTEN and LXR, and highlights LXRs as metabolic gatekeepers that are able to constrain PCa progression.Treatment of prostate cancer, especially in its advanced stage, is still challenging; therefore, strategies to prevent metastatic dissemination are of great interest. Here the authors reveal a crucial role for liver X receptors in suppressing prostate carcinogenesis and metastatic progression in PTEN-null tumors.
晚期前列腺癌（PCa）是一项临床挑战，因为目前尚无治愈性疗法。在此背景下，深入了解PCa的转移和耐药机制是一个重要问题。由于磷酸酶和张力蛋白同源物（PTEN）缺失是此类癌症中最常见的基因损伤，我们研究人类数据集以寻找在这种情况下能够限制癌症进展的机制。在此，我们报告了一种在PCa中与PTEN缺失紧密相关的肝脏X受体（LXR）特征。相应地，在Pten基因缺失的小鼠前列腺癌中，LXR信号通路失调。在Pten基因缺失的小鼠中对LXR进行基因敲除，会加剧PCa的侵袭性和转移扩散，这涉及间充质转化和基质金属蛋白酶的积累。从机制上讲，PTEN缺失通过胆固醇从头合成的失调来控制LXR的转录活性，导致内源性LXR配体的积累。因此，我们的研究揭示了连接PTEN和LXR的功能回路，并强调LXR作为能够限制PCa进展的代谢守门人。前列腺癌的治疗，尤其是晚期前列腺癌的治疗，仍然具有挑战性；因此，预防转移扩散的策略备受关注。在此，作者揭示了肝脏X受体在抑制PTEN基因缺失肿瘤中的前列腺癌发生和转移进展方面的关键作用。
