Hypoxia upregulates Hsp90α expression via STAT5b in cancer cells

Hsp90 alpha is a molecular chaperone protein involved in the structural maturation of oncogenic signaling proteins. Hsp90 was recently identified as an anticancer target; various studies are ongoing to find ways for managing cancer through Hsp90 alpha. However, this approach is limited by reported side-effects. Hypoxia is a hallmark of solid tumors, including those of breast cancer and the extent of tumor hypoxia is associated with resistance to treatment and poor prognosis. One of the major signaling pathways in cancer cells, the Jak2/STAT5b pathway, has been found to be closely correlated with hypoxia. The objective of this study was to investigate the role of Jak2/STAT5b in the regulation of Hsp90 alpha expression so that Hsp90 alpha targeting can be achieved indirectly by modulating the Jak2/STAT5b pathway. We examined the role of the Jak2/STAT5b pathway in the expression of Hsp90o under hypoxic conditions by immunoblotting, reporter gene assays, EMSA and RNA interference analysis. With the help of in vivo models, we also analyzed the expression of Hsp90 alpha in different parts of solid tumor tissues. We found a close association between hypoxic stress and Hsp90 alpha expression. We also determined that STAT5b regulates the expression of Hsp90 alpha during hypoxic stimulation. Under hypoxic conditions the expression of Hsp90 alpha and STAT5b were proportional. siRNA analysis and nucleotide analysis showed that the promoter of Hsp90 alpha has a STAT5b binding domain. Our work confirmed that STAT5b is one of the transcription factors that regulate Hsp90 alpha. We, therefore, concluded that under hypoxic conditions, the Jak2/STAT5b pathway regulates Hsp90 alpha expression and it could serve as a promising target for the treatment of solid tumors.