piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis
piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis
复制标题
PIWIL1作为后期促进复合物/环体驱动胰腺癌转移的共激活剂的独立于piRNA的功能
DOI：
10.1038/s41556-020-0486-z
复制
发表时间：
2020-03-16
影响因子：
21.3
通讯作者：
Liu, Mo-Fang
中科院分区：
文献类型：
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作者：
Li, Feng;Yuan, Peng;Liu, Mo-Fang
Piwi蛋白通常被限制在生殖细胞中，通过与Piwi相互作用RNAs(PiRNAs)结合来抑制转座子，但它们在许多类型的人类癌症中也经常被激活。一个很大的谜题是在癌细胞中缺乏显著的诱导相应的piRNAs，正如我们在这里在人类胰腺导管腺癌(PDAC)中所记录的那样，这意味着这些生殖系特异的蛋白质以某种方式被劫持，通过不同的作用模式促进肿瘤的发生。在这里，我们证明了在没有piRNAs的情况下，PDAC中的人PIWIL1通过激活后期促进复合体/环体(APC/C)E3复合体作为癌蛋白发挥作用，然后靶向关键的细胞黏附相关蛋白Pinin，以促进PDAC的转移。这与依赖piRNA的PIWIL1泛素化和APC/C在精子发生后期的去除形成了鲜明对比。这些发现揭示了一种依赖piRNA的机制，将PIWIL1从精子细胞的底物转换为人类癌细胞中APC/C的共同激活剂。
Piwi proteins are normally restricted in germ cells to suppress transposons through associations with Piwi-interacting RNAs (piRNAs), but they are also frequently activated in many types of human cancers. A great puzzle is the lack of significant induction of corresponding piRNAs in cancer cells, as we document here in human pancreatic ductal adenocarcinomas (PDACs), which implies that such germline-specific proteins are somehow hijacked to promote tumorigenesis through a different mode of action. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. This is in contrast to piRNA-dependent PIWIL1 ubiquitination and removal by APC/C during late spermiogenesis. These findings unveil a piRNA-dependent mechanism to switch PIWIL1 from a substrate in spermatids to a co-activator of APC/C in human cancer cells.