Using DAVID, we found that hypermethylated genes in ESC cells are mostly enriched with the regulation of cell cycle (FZR1, E2F5
, BOP1, TRRAP, CDK4, JUNB, etc.), cell death (SIVA1, MCL1, YPEL3, ARF6, UBQLN1, SHF, CIAPIN1, APLP1, GPX1, CASP3, etc.), and mRNA metabolic process (SCAF1, FIP1L1, STRAP, RBM15B, CWC15, XAB2, YBX1, AUH, SF3B2, APLP1, HNRNPL, etc.); the hypomethylated genes are enriched with functions related to ATP synthesis (ATP6V1F, ATP6V1C1, ATP6V0C, ATP6V1A, ATP6V0E, ATP6V1E1, ATP5C1, etc.) and mitochondrial ribosome (MRPL15, MRPL27, MRPL16, MRPL36, MRPL39, MRPL34, DAP3, etc.) (Excel Sheet S2).
revealed that HMGA1, HMGA2, IGF2BP2, HIF3A, ARID3A, and E2F5
were the most highly induced targets of let-7 microRNAs in the context of intestinal homeostasis .
For example, the let-7 family has been shown to repress multiple genes involved in cell cycle, cell apoptosis, and cell proliferation, including CCNA2, CDC34, AURA/STK6, AURKB/ STK12, E2F5
, and CDK8 .
revealed in vitro that miR-132 inhibited cell proliferation, invasion, and migration in ovarian cancer by targeting the transcription factor E2F5
In colorectal cancer (CRC), hsa_circ_001569 acts as the positive regulator of cell proliferation and invasion via "sponging event" of miR-145, which upregulates functional targets of E2F5
, BAG4, and FMNL2 .
HCC with recurrence exhibited enrichment of upregulated genes mapping to signaling or disease pathways associated with cell cycle regulators (CDKN2B, E2F2, E2F5
, GNL3, HDAC2, MDM2, MYC, and PA2G4), including the genes that encode the proteins that control molecular mechanisms of cancer (FANCD2, FZD3, PLCB1, and PMAIP1).
Triptolide downregulated the cell cycle-related genes E2F2 E2F3, E2F5
, CDKN2C, CDK7, CDC23, and SMAD3; the MAPK signaling pathway genes FOS, CASP3, JUND, KRAS, MAP2K2; and the Wnt signaling pathway genes WNT4, MYC, and AXIN2.
Notably, circ_001569 did not directly affect miR-145 expression, but through a sponge mechanism it inhibited its posttranscriptional activity; accordingly, it upregulated its targets E2F5
(E2F transcription factor 5), BAG4 (BCL2-associated athanogene 4), and FMNL2 (formin-like 2), which were responsible for cell proliferation and invasion promotion by circ_001569 .
Let-7a elevates p21 (CDKN1A) levels via UHRF2 (ubiquitin-like with PHD and ring finger domains 2) inhibition and suppresses the growth of A549 lung cancer cells , whereas miR-128-2 posttranscriptionally targets E2F5
and leads to the abrogation of its repressive activity on p21 (waf1) transcription in a human NSCLC cell line (H1299) .
Hsa_ circ_001569 may act as a miR-145 sponge and represses the transcriptional activities of miR-145, enabling upregulation of miR-145 target genes E2F5
, BAG4, and FMNL2.
hsa_circ_001569 was reported to act as a positive regulator of proliferation and invasion of CRC cells; it functions as a sponge of miR-145, and therefore, targets upregulated miR-145, such as E2F5
, BAG4, and FMNL2 .