Polycomb-Mediated Loss of miR-31 Activates NIK-Dependent NF-κB Pathway in Adult T Cell Leukemia and Other Cancers

Abstract

Constitutive NF-κB activation has causative roles in adult T cell leukemia (ATL) caused by HTLV-1 and other cancers. Here, we report a pathway involving Polycomb-mediated miRNA silencing and NF-κB activation. We determine the miRNA signatures and reveal miR-31 loss in primary ATL cells. MiR-31 negatively regulates the noncanonical NF-κB pathway by targeting NF-κB inducing kinase (NIK). Loss of miR-31 therefore triggers oncogenic signaling. In ATL cells, miR-31 level is epigenetically regulated, and aberrant upregulation of Polycomb proteins contribute to miR-31 downregulation in an epigenetic fashion, leading to activation of NF-κB and apoptosis resistance. Furthermore, this emerging circuit operates in other cancers and receptor-initiated NF-κB cascade. Our findings provide a perspective involving the epigenetic program, inflammatory responses, and oncogenic signaling.

MicroRNA-31 Is a Transcriptional Target of Histone Deacetylase Inhibitors and a Regulator of Cellular Senescence

“…Negative regulation of BMI1 and EZH2 by miR-31 appears to be indirect, as none of the miRNA target prediction bioinformatics programs predict the presence of complementary seed sequences of miR-31 in BMI1 or EZH2 mRNAs. miR-31 is a pleiotropically acting miRNA with more than 200 predicted mRNA that can be targeted by miR-31 (7,8,50,54). We experimentally confirmed down-regulation of several possible targets of miR-31, such as NF-B inducing kinase, ITGA5, SEPHS1, RSBN1, and TFDP1.…”

“…Indeed it is known that miR-31 can target tumor suppressors LATS2 and PPP2R2A in lung cancer cells (58). Nonetheless, a vast majority of miR-31 targets are pro-oncogenic factors including cell cycle promoting factors such as E2Fs (52), oncogenic tyrosine kinases such as MET and SRC (50), and genes that are up-regulated in metastatic cancer cells (7,8,50,54).…”

“…Previously it has been reported that miR-31 is negatively regulated by EZH2 and PRC2 (8,50). It has been also reported that the miR-31 expression is lost in melanomas, and that its genetic and epigenetic loss in cancers, in particular melanoma may lead to a feed-forward up-regulation of EZH2 (50).…”

“…It can target several cancer and metastasis relevant targets such as Fzd3, ITGA5, MMP16, RDX, and RhoA (7). In addition, miR-31 was recently shown to target NF-B inducing kinase and to be negatively regulated by the polycomb group (PcG) protein EZH2 in adult T cell leukemia cells (8). The PcG protein EZH2 is a constituent of polycomb repressive complex (PRC) 2, which is thought to work in concert with PRC1 (9,10).…”

Reducing the global burden of HTLV-1 infection: An agenda for research and action

“…-genes promoting viral replication and persistence (Tax and HBZ) (Matsuoka and Jeang, 2007); -modes of viral entry and replication (infectious and mitotic cycles) (Ghez et al, 2010;Boxus et al, 2012;Gillet et al, 2011Gillet et al, , 2013Sibon et al, 2006); -genomic and epigenetic mechanisms leading to ATL (oncogenic stress, driver mutations) (Kataoka et al, 2015;Yamagishi et al, 2012); -the role of the immune response in the control of infection (Asquith and Bangham, 2008); -the pathogenic potential of HTLV-2, -3 and -4 (Calattini et al, 2006).…”