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

Area of Science:

• Epigenetics
• Molecular Oncology
• Cellular Biology

Background:

• Aberrant epigenetic modifications influence tumor progression.
• The role of histone demethylase KDM6B in thyroid carcinoma (THCA) is currently unknown.

Purpose of the Study:

• To investigate the role and mechanism of KDM6B in THCA.
• To explore KDM6B as a potential therapeutic target in THCA.

Main Methods:

• MTT assay for screening and validation.
• In vitro and in vivo assays for proliferation, migration, and invasion.
• Chromatin immunoprecipitation (ChIP) and Western blotting to analyze protein interactions and modifications.

Main Results:

• KDM6B promotes THCA proliferation, migration, and invasion.
• E2F1 directly regulates KDM6B expression, and KDM6B partially mediates E2F1's oncogenic functions.
• KDM6B demethylates H3K27me3 at the TFEB promoter, activating TFEB and downstream lysosomal genes, thereby enhancing autophagy.
• KDM6B enhances autophagy (evidenced by p62 and Beclin-1) and accelerates THCA progression.
• Targeting autophagy with 3-MA significantly inhibits KDM6B-high THCA growth.

Conclusions:

• KDM6B is an essential epigenetic regulator and autophagy promoter in THCA.
• The E2F1/KDM6B/TFEB axis represents a novel therapeutic vulnerability for THCA treatment.