Telomerase reverse transcriptase (TERT) activates transcription of miR500A to inhibit Hedgehog signaling and promote cell invasiveness.

Telomerase reverse transcriptase (TERT) maintains telomere homeostasis, thus ensuring chromosome stability and cell proliferation. In addition, several telomere-independent functions of human TERT have been described. In this study, we report that TERT binds directly to the TCF binding elements (TBE) located upstream of the oncomiR miR500A, and induces its transcription. This function was independent of the telomerase activity, as shown with experiments using catalytically inactive TERT and inhibitors of TERT and TERC (the TERT RNA component). miR500A was in turn found to target three key components of the Hedgehog signaling pathway: Patched 1 (PTCH1); Gli family zinc finger 3 (GLI3); and Cullin 3 (CUL3), thereby promoting cell invasion. Our results point to the crucial role of the TERT-miR500A-Hedgehog axis in tumor aggressiveness and highlight the therapeutic potential of targeting noncanonical TERT functions in cancer.