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Endogenous retroviruses drive KRAB zinc-finger family protein expression for tumor suppression

By Jumpei Ito, Izumi Kimura, Andrew Soper, Alexandre Coudray, Yoshio Koyanagi, Hirofumi Nakaoka, Ituro Inoue, Priscilla Turelli, Didier Trono, Kei Sato

Posted 03 Feb 2020
bioRxiv DOI: 10.1101/2020.02.02.931501

Numerous genes are aberrantly expressed in tumors, but its cause remains unclear. Human endogenous retroviruses (HERVs) are repetitive elements in the genome and have a potential to work as enhancers modulating adjacent genes. Since numerous HERVs are activated epigenetically in tumors, their activation could alter gene expression globally in tumors and change the tumor characteristics. Here, we show the HERV activation in tumors is associated with the upregulation of hundreds of transcriptional suppressors, Kruppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by the adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Many KZFPs could suppress the progressive characteristics of cancer cells by downregulating genes related to the cell cycle and cell-matrix adhesion. Our data suggest that HERV activation in tumors drives the concerted expression of KZFP genes for tumor suppression.

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