Lnc-HZ06 down-regulates HIF1α protein levels in CoCl2-exposed hypoxic trophoblast cells and villous tissues of miscarriage patients

Hypoxia plays significant roles in various biological processes. In recent study, we have found that a novel lnc-HZ06 promotes the SUMOylation of HIF1α in hypoxic human trophoblast cells. Since environmental cobalt (Co) exposure causes trophoblast cell hypoxia, whether and how lnc-HZ06 might regulate the protein levels of HIF1α, an important biomarker of hypoxia, in CoCl₂-exposed hypoxic trophoblast cells is still unexplored. In this study, we find that lnc-HZ06 is highly expressed in CoCl₂-exposed trophoblast cells; and lnc-HZ06 further down-regulates HIF1α protein levels. In details, (1) lnc-HZ06 up-regulates METTL14 (methyltransferase-like 14) and increases m⁶A (N6-methyladenosine) RNA modification levels on VHL (a ubiquitin E3 ligase of HIF1α) mRNA, and thus enhances its mRNA stability and up-regulates VHL mRNA levels. (2) VHL interacts with the SUMOylated HIF1α and promotes the ubiquitination of HIF1α, and finally lnc-HZ06 promotes the ubiquitination degradation of HIF1α protein in CoCl₂-exposed hypoxic trophoblast cells. Therefore, lnc-HZ06 promotes VHL-mediated HIF1α protein degradation and down-regulates HIF1α protein levels. The cellular mechanisms in hypoxic trophoblast cells were partially consistent to those in villous tissues of patients with unexplained miscarriage (UM), expect for no significantly different Co content in UM and healthy control (HC) villous tissues. Collectively, this study discovers novel regulatory roles of lnc-HZ06 and m⁶A modification and post-translational modification (SUMO/Ubiquitin) in HIF1α protein levels in hypoxic human trophoblast cells.