piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis

• Published in: Nature cell biology Vol. 22; no. 4; pp. 425 - 438
• Main Authors: Li, Feng, Yuan, Peng, Rao, Ming, Jin, Chun-Hui, Tang, Wei, Rong, Ye-Fei, Hu, Yun-Ping, Zhang, Fengjuan, Wei, Tao, Yin, Qi, Liang, Tingbo, Wu, Ligang, Li, Jinsong, Li, Dangsheng, Liu, Yingbin, Lou, Wenhui, Zhao, Shuang, Liu, Mo-Fang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2020; Nature Publishing Group
• Subjects: 13/109; 13/31; 13/51; 13/89; 14/5; 38/77; 38/91; 631/326; 631/67; 631/80; 692/699; 82; 82/1; 82/58; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenomatous polyposis coli; Anaphase; Anaphase-promoting complex; Anaphase-Promoting Complex-Cyclosome - genetics; Anaphase-Promoting Complex-Cyclosome - metabolism; Animals; Argonaute Proteins - genetics; Argonaute Proteins - metabolism; Biomedical and Life Sciences; Cancer; Cancer Research; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell adhesion; Cell adhesion & migration; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Biology; Cell Line, Tumor; Cell Proliferation; Development and progression; Developmental Biology; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic regulation; Germ cells; Health aspects; Humans; Life Sciences; Lymphatic Metastasis; Male; Metastases; Metastasis; Mice; Mice, Knockout; Mice, Nude; Mode of action; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology, Experimental; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Physiological aspects; Proteins; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Spermatids; Spermatogenesis - genetics; Spermiogenesis; Stem Cells; Substrates; Transcriptional coactivators; Transposons; Tumorigenesis; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Xenograft Model Antitumor Assays; China
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-020-0486-z

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. Li et al. report that PIWIL1 executes a piRNA-independent function in promoting pancreatic cancer metastasis. Mechanistically, PIWIL1 acts as a co-activator for the ubiquitin E3 ligase APC/C.