AEBP1-GLI1 pathway attenuates the FACT complex dependency of bladder cancer cell survival

Abstract

The facilitates chromatin transcription (FACT) complex is composed of SSRP1 and SUPT16H subunits and participates in nucleosomal reorganization; hence, FACT inhibitors are considered promising therapeutics for malignant tumors. Here, we show that adipocyte enhancer binding protein 1 (AEBP1) attenuates the dependency of bladder cancer cell survival on the FACT complex via the expression of GLI1, a pivotal transcription factor in Hedgehog signaling. In AEBP1-high expressing bladder cancer cell lines, AEBP1 knockdown inhibited cellular proliferation and induced the marker expression of apoptosis and DNA damage/replication stress. RNA-sequencing revealed that AEBP1 knockdown suppressed the expression of SSRP1 and SUPT16H; however, the knockdown of both subunits was less effective than AEBP1 knockdown in inducing apoptosis or DNA damage markers in AEBP1-high expressing cells. AEBP1 knockdown reduced the protein levels of GLI1, and treatment with the GLI-specific inhibitor GANT61 induced markers that were not suppressed by the forced expression of AEBP1. These findings suggest that AEBP1-mediated GLI1 expression reduces the FACT complex dependency of bladder cancer cell survival.