UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression
UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression
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DOI：
10.1038/onc.2012.3
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发表时间：
2012-12-01
期刊：
影响因子：
8
通讯作者：
Colantuoni, V.
中科院分区：
文献类型：
--
作者：
Sabatino, L.;Fucci, A.;Colantuoni, V.
过氧化物酶体增殖物激活受体γ（PPARG）失活已被确定为结直肠癌（CRC）进展的重要步骤，尽管所涉及的事件已部分澄清。UHRF 1正在成为一种辅助因子，协调肿瘤抑制基因的表观遗传沉默，但其在CRC中的作用仍然难以捉摸。在这里，我们报告说，UHRF 1负调节PPARG，并与更高的增殖，克隆和迁移潜力。一致地，UHRF 1异位表达通过其在PPARG启动子上的募集诱导PPARG抑制，促进DNA甲基化和组蛋白抑制性修饰。一致的是，UHRF 1敲低导致PPARG重新激活，伴随着阳性组蛋白标记和DNA去甲基化，证实了其在PPARG沉默中的作用。UHRF 1过表达以及PPARG沉默赋予更高的生长速率和类似于上皮-间充质转化中发生的表型特征。在我们的110例散发性CRC中，高UHRF 1表达肿瘤的特征是未分化表型、较高的增殖率和仅在晚期III-IV期临床结局较差。此外，在体外发现的与PPARG的负相关关系在体内被检测到，并且UHRF 1预后意义似乎与PPARG低表达密切相关，如在独立数据集中显著验证的。结果表明，UHRF 1调节PPARG沉默，这两个基因似乎是一个复杂的调控网络的一部分。这些发现表明，UHRF 1和PPARG之间的关系可能在CRC进展中具有相关作用。Oncogene（2012）31，5061-5072; doi：10.1038/onc.2012.3; 2012年1月30日在线发表
Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulates PPARG and is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression induces PPARG repression through its recruitment on the PPARG promoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role in PPARG silencing. UHRF1 overexpression, as well as PPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III-IV. In addition, the inverse relationship with PPARG found in vitro is detected in vivo and UHRF1 prognostic significance appears closely related to PPARG low expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulates PPARG silencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 and PPARG may have a relevant role in CRC progression. Oncogene (2012) 31, 5061-5072; doi:10.1038/onc.2012.3; published online 30 January 2012