Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation.
Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation.
复制标题
DOI：
10.7554/elife.30862
复制
发表时间：
2017-11-16
期刊：
影响因子：
7.7
通讯作者：
Arora VK
中科院分区：
文献类型：
--
作者：
Halstead AM;Kapadia CD;Bolzenius J;Chu CE;Schriefer A;Wartman LD;Bowman GR;Arora VK
RXRA作为异源二聚体的一部分与14种其他核受体调节转录，包括过氧化物酶体增殖物激活受体（PPARs）。TCGA的分析提出了过度活跃的PPAR信号传导（无论是由于PPAR γ基因扩增还是RXRA热点突变（S427 F/Y））导致20-25%的人类膀胱癌的可能性。在这里，我们的特点突变体RXRA，证明它诱导增强子/启动子活性的背景下，RXRA/过氧化物酶体增殖物激活受体异源二聚体在人膀胱癌细胞。结构-功能研究表明，RXRA取代通过与PPARs中发现的末端酪氨酸的芳香族相互作用变构调节PPARAF 2结构域。在小鼠尿路上皮类器官中，在同时发生肿瘤抑制因子丢失的情况下，PPAR激动足以驱动生长因子非依赖性生长。类似地，突变体RXRA刺激Trp 53/Kdm 6a无效膀胱类器官的生长因子非依赖性生长。突变体RXRA驱动的膀胱癌生长可通过抑制PPAR逆转，支持PPAR作为膀胱癌的靶向驱动因子。膀胱癌是美国第六大常见癌症。目前，晚期膀胱癌的治疗选择仅限于化疗和免疫疗法，这两种疗法仅对部分患者有益。许多其他类型的癌症可以用对这些癌细胞中发现的基因突变具有特异性的药物进行治疗，通常使治疗更有效，副作用更少。5-8%的膀胱癌患者的基因发生突变，产生一种名为RXRA的蛋白质。这种蛋白质与自身或与其他蛋白质合作来控制基因活性。然而，目前尚不清楚突变的RXRA蛋白在膀胱癌细胞中的作用。Halstead等人研究了人类膀胱癌细胞和在实验室中从小鼠膀胱细胞中生长的“迷你膀胱”中的RXRA突变。生物化学实验表明，突变的RXRA蛋白导致其一组伴侣蛋白异常高的活性，称为过氧化物酶体增殖物激活受体（PPARs）。PPARs反过来又打开了帮助癌细胞生长和繁殖的基因。突变体RXRA与PPARs结合的计算模拟在分子水平上揭示了这种激活是如何发生的。最后，Halstead等人使用阻断PPARs活性的化学物质来阻止含有RXRA突变的小鼠迷你膀胱中细胞的生长。这些发现表明，具有RXRA突变的膀胱癌患者可能受益于抑制PPARs的治疗。这种疗法也可以使大约15-20%的膀胱癌患者受益，他们没有RXRA突变，但有过度活跃的PPARs。虽然有一些化学物质可以阻断PPARs的活性，但在它们被用于治疗癌症之前，还需要更多的研究来完善它们。
RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20–25% of human bladder cancers. Here, we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In mouse urothelial organoids, PPAR agonism is sufficient to drive growth-factor-independent growth in the context of concurrent tumor suppressor loss. Similarly, mutant RXRA stimulates growth-factor-independent growth of Trp53/Kdm6a null bladder organoids. Mutant RXRA-driven growth of urothelium is reversible by PPAR inhibition, supporting PPARs as targetable drivers of bladder cancer. Bladder cancer is the sixth most common type of cancer in the United States. At the moment, treatment options for advanced bladder cancer are limited to chemotherapy and immunotherapy, both of which benefit only some patients. Many other types of cancer can be treated with drugs that are specific to genetic mutations found in those cancer cells, often making the treatments more efficient with fewer side effects. Between 5–8% of people with bladder cancer have a mutation in the gene that produces a protein called RXRA. This protein partners with itself or with other proteins to control gene activity. However, it was not clear what mutant RXRA proteins do in bladder cancer cells. Halstead et al. studied the RXRA mutation in human bladder cancer cells and “mini-bladders” grown in the laboratory from mouse bladder cells. Biochemical experiments showed that the mutant RXRA protein causes abnormally high activity in one group of its partner proteins, called peroxisome proliferator-activated receptors (PPARs). The PPARs, in turn, switch on genes that help cancer cells to grow and multiply. Computational simulations of the mutant RXRA binding to PPARs revealed, at a molecular level, how this activation occurs. Lastly, Halstead et al. used chemicals that block the activity of PPARs to stop the growth of cells in the mouse mini-bladders that contained the RXRA mutation. These findings suggest that bladder cancer patients with the RXRA mutation may benefit from therapies that inhibit PPARs. Such therapies could also benefit the approximately 15–20% of people with bladder cancer who do not have the RXRA mutation but who do have over-active PPARs. Although there are chemicals that block the activity of PPARs, more research is needed to refine them before they can be used to treat cancer.