Hypoxia increases RCC stem cell phenotype via altering the androgen receptor (AR)-lncTCFL5-2-YBX1-SOX2 signaling axis

Early studies indicated that the androgen receptor (AR) could promote renal cell carcinoma (RCC) development and metastasis, but its linkage to RCC progression under hypoxia, remains unclear.

Here we found AR expression in RCC cells decreased in response to hypoxia, which might then lead to increase the cancer stem cells (CSC) phenotype through the lncTCFL5-2-modulated YBX1/SOX2 signals. The consequences of such hypoxia-modulated AR/lncTCFL5-2/YBX1/SOX2 signals ablity to alter the CSC phenotype might render RCC cells more resistant to targeted therapy with Sunitinib. Mechanism dissection revealed that AR might alter the lncTCFL5-2/YBX1/SOX2 signaling through transcriptional suppression of the lncTCFL5-2 expression via the AR-response-elements (AREs) on the lncTCFL5-2 promoter. The lncTCFL5-2 interacts with YBX1 to increase its stability, which in turn increases SOX2 expression at a transcriptional level via the YBX1-response-elements (YBX1Es) on the SOX2 promoter. The in vivo mouse model with orthotopic xenografts of RCC cells also validates the in vitro data, and a human RCC sample survey demonstrated the clinical significance of the AR/lncTCFL5-2/YBX1/SOX2 signaling axis for the RCC prognosis, likely as a result of regulating CSC phenotypes.

Together, these findings suggest that hypoxia may increase the RCC CSC phenotype via altering the AR/lncTCFL5-2/YBX1/SOX2 signaling axis and a potential therapy to target this newly identified signal perhaps may help improve the targeted therapy with Sunitinib to better suppress RCC progression.