piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis
Authors: Wei Tang
Peng Yuan
Tao Wei
Feng Li
Ming Rao
Dangsheng Li
Chun-Hui Jin
Wenhui Lou
Ye-Fei Rong
Shuang Zhao
Mo-Fang Liu
Fengjuan Zhang
Yingbin Liu
Tingbo Liang
Qi Yin
Yun-Ping Hu
Ligang Wu
Jinsong Li
Journal: Nature Cell Biology (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Piwi proteins; piRNAs; human cancers; pancreatic ductal adenocarcinomas (PDACs); PIWIL1
Affiliations: State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences-University of Chinese Academy of Sciences, Shanghai, China., School of Life Science and Technology, Shanghai Tech University, Shanghai, China., The Animal Core Facility, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China., Department of Pancreatic Surgery, Zhong Shan Hospital, Shanghai, China., Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China., State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences-University of Chinese Academy of Sciences, Shanghai, China., State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences-University of Chinese Academy of Sciences, Shanghai, China. ., School of Life Science and Technology, Shanghai Tech University, Shanghai, China. .

Abstract:  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. 

Retracted: No

PubPeer comments:
 Brought to my attention by a reader. Figure 4E and 6E * Some cells appear to be visible outside the boxes in Figure 4E. * Green shapes: Panel PIWIL1 in Figure 4E appears to show an overlap with panel Mock in Figure 6E, albeit at a different rotation. ![file] Comparing the two panels, it appears that some extra cells might be visible in Figure 6E that are not visible in Figure 4E. Shown here with brown triangles. ![file] , 
 Dear Dr. Bik, Thank you for your comment on our paper. We have carefully checked the indicated trans-well images in Figures 4E and 6E and confirmed an error in Figure 6E. Fortunately, we have saved all the original images for the trans-well experiments that belong to Figures 4E and 6E in our computers and found that the mistake likely resulted from the incorporation of wrong figure panel due to high similarity between the two sets of data images in the original data folder. Specifically, the student inadvertently used an image for the u201cMocku201d panel in Figure 6E from the original images for the u201cPIWIL1u201d panel in Figure 4E. We are now working with the journal to issue a correction to fix the problem. We will update you the information later. Many thanks again. Mofang , 
 Thank you, Dr. Liu, for looking into this and for correcting the error. , 
 Correction, April 2020: https: www.nature.com articles s41556-020-0520-1  In the version of this article originally published, the authors inadvertently used a source image of the u201cPIWIL1u201d panel in Fig. 4e as an image for the u201cMocku201d panel in Fig. 6e. The image of u201cMocku201d panel in Fig. 6e has now been replaced with the correct one. Additionally, the source data for the full dataset of Figs. 4e and 6e have been deposited to Figshare , and the figure legends have been amended to reflect this in Figs. 4 and 6, respectively. The errors have been corrected in the HTML and PDF versions of the paper. ,