E2F1-driven histone demethylase KDM6B enhances thyroid malignancy via manipulating TFEB-dependent autophagy axis

Abstract

Aberrant epigenetic modifications or events regulate autophagy to influence tumor progression, which has gained increasing attention. KDM6B is an essential histone demethylase that participates in multiple processes of tumors, but its role in thyroid carcinoma (THCA) remains to be unknown. Here, in this study, we used the MTT assay to screen and validate that KDM6B is an essential demethylase for THCA. KDM6B promotes THCA proliferation, migration, invasion in vitro and in vivo. Transcriptional factor E2F1 directly binds to the promoter region of KDM6B and regulates its mRNA levels in THCA. E2F1 partially depended on KDM6B to exert its oncogenic functions. Mechanistically, KDM6B binds to TFEB promoter region and mediates the demethylation of H3K27me3. KDM6B depended on TFEB to activate a series of lysosomal-related genes. KDM6B enhances autophagy process, as evidenced by elevated p62 and Beclin-1 proteins. KDM6B depended on TFEB-driven autophagy activity to accelerate THCA progression. Lastly, targeting autophagy with 3-MA could notably abrogate growth of KDM6Bhigh THCA, but has mild influence on KDM6Blow THCA. Together, this study identified KDM6B as an essential epigenetic regulator for THCA, functioning as an autophagy regulator. The fundamental mechanisms underlying E2F1/KDM6B/TFEB axis provided novel vulnerabilities for THCA treatment.