HIF-1α forms regulatory loop with YAP to coordinate hypoxia-induced adriamycin resistance in acute myeloid leukemia cells.

Despite the improvement in acute myeloid leukemia (AML) treatments, most patients had a poor prognosis and suffered from chemoresistance and disease relapse. Therefore, there is an urgent need for elucidation of mechanism(s) underlying drug resistance in AML. In the present study, we found that AML cells showed less susceptibility to adriamycin (ADR) in the presence of hypoxia, while inhibition of hypoxia-inducible factor 1α (HIF-1α) by CdCl can make AML cells re-susceptibile to ADR even under hypoxia. Moreover, HIF-1α is overexpressed and plays an important role in ADR-resistance maintenance in resistant AML cells. We further found hypoxia or induction of HIF-1α can significantly upregulate yes-associated protein (YAP) expression in AML cells, and resistant cells express a high level of YAP. Finally, we found that YAP may not only enhance HIF-1α stability but also promote HIF-1α's activity on the target gene pyruvate kinase M2. In conclusion, our data indicate that HIF-1α or YAP may represent a therapeutic target for overcoming resistance toward adriamycin-based chemotherapy in AML.