Chinese Scientists Found PIWIL1 as a Novel co-activator for APC/C to Promote Pancreatic Cancer Metastasis

A team of scientists led by Dr. LIU Mofang at the Center for Excellence in Molecular Cell Science-Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, have found that PIWIL1 functions as a novel co-activator for Anaphase Promoting Complex/Cyclosome (APC/C) E3 complex to promote pancreatic cancer metastasis. This work entitled “piRNA-independent function of PIWIL1 as a co-activator for anaphase promoting complex/cyclosome to drive pancreatic cancer metastasis” was online published in Nature Cell Biology on March 16, 2020. The work was collaborated with Drs. LOU Wenhui (Zhong Shan Hospital, Shanghai), LIU  Yingbin (Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine), LI Dangsheng (SIBCB), LI Jinsong (SIBCB) and WU Ligang (SIBCB).

 

The evolutionarily conserved PIWI proteins belong to the Piwi clade of the Argonaute family, each of which is specifically expressed in animal germlines and essential for germline development in animals. Increasing evidence shows that PIWI proteins, in complex with Piwi-interacting RNAs (piRNAs), silence transposable elements at both epigenetic and post-transcriptional levels, thereby protecting the genome integrity in animal germ cells.

 

Additionally, the PIWI/piRNA machinery has also been reported to regulate protein coding genes in germ cells. The human genome encodes four Piwi paralogs, including Piwil1 (Hiwi), Piwil2 (Hili), Piwil3, and Piwil4 (Hiwi2), all of which are primarily expressed in testis.

 

However, Piwil1andPiwil2have been shown to be aberrantly induced in various types of human cancers. This exemplifies the induction of a large variety of testis-restricted genes in human cancers, which are collectively referred to as cancer-testis antigens (CTAs). In contrast to the great advances in understanding of the functions of PIWI proteins in germlines, their actions in cancer cells remain largely unclear.

 

The researchers discover that PIWIL1, but not piRNAs, is aberrantly expressed in human pancreatic ductal adenocarcinomas (PDAC) cells and functions to promote pancreatic tumor growth and metastasis. The group previously show that piRNA-loaded PIWIL1 is ubiquitylated and removed by the APC/C-ubiquitin pathway in spermatids.

 

Intriguingly, their present study reveals that unliganded PIWIL1 acts as a co-activator of APC/C to promote PDAC metastasis. The primary function of APC/C is to govern cell cycle progression through proteasome-dependent degradation of key cell cycle regulators, such as cyclins and CDK inhibitors. Importantly, its activity is tightly controlled by co-activators (such as Cdc20 and Cdh1), while its dysregulation has been implicated in multiple human diseases, including cancers. They further demonstrate that the proteolysis of cell-cell adhesion protein Pinin by APC/C^PIWIL1 is functionally required for PIWIL1 action onPDAC metastasis. These findings have thus uncovered an unprecedented oncogenic mechanism by which an abnormally induced PIWI protein in human cancers promotes metastasis after switching its role from a substrate to co-activator of APC/C.

 

This study was supported by the grants from the Chinese Academy of Sciences, National Natural Science Foundation of China, Ministry of Science and Technology, and Science and Technology Commission of Shanghai Municipality.

 

Reference: https://www.nature.com/articles/s41556-020-0486-z