Figure 1.

Schematic of NORAD molecular interacting partners in BC, emphasizing cellular localization, and impact on cancer progression. Solid lines indicate direct binding, dotted lines indicate indirect, undescribed or untested experimentally binding mechanism in BC, where circular ends refer to co-expression, cut ends to repression and pointed ends to promotion of expression. The impact on BC progression is also described, specifically how these interactions are reflected in cellular viability, proliferation, migration, invasion, apoptosis, metastatic capacity and stemness. In the nucleus, YAP/TAZ-TEAD and NuRD repress NORAD transcription, increasing migration and invasion of BC cells. NORAD also affects histone γH2AX expression and the consequent DNA damage response (DDR). In the cytoplasm, NORAD has increased expression and m6A methylation and is consequently secreted in exosomes to influence other cell types such as macrophage polarization into M2 protumoral phenotype. NORAD sequesters PUM1 and PUM2, leading to repression of c-JUN transcription and decreased levels of PTEN, FOXO1, NRAS, RALGAPB and PSMG4 transcripts in the cytoplasm, where the latter two co-express with NORAD. MiR-323a-3p also binds PUM1 along with NORAD, resulting in increased NRP-1 expression in the mitochondria, which is in turn repressed by miR-376a. eIF2 downstream effectors PERK on the rough endoplasmic reticulum and ATF4 are consequently induced. PUM2, sequestered by NORAD, also represses INSM1, which represses SASH1 transcription, lowering PI3K and AKT levels. Independently of PUM, in the cytoplasm, NORAD represses RHOA, miR-155-5p (inducing nuclear SOCS1 expression) and miR-590-3P (decreasing Golgi apparatus GOLPH3), induces TGF-β (increasing nuclear RUNX2) and co-expresses with MAPK14. NORAD also represses S100P transcription, decreasing S100P binding to TP53 and IQGAP1 proteins, and the amount of IQGAP1 in the membrane. Subcellular localization was based on UniProt data [44]. Created with BioRender.com.