HOXB13 as a Lineage-Restricted Chromatin Regulator Linking Androgen Signaling, Epigenetic Remodeling, Metabolic Reprogramming, and Kinase Signaling in Prostate Cancer Progression

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Prostate cancer progression is shaped by dynamic interactions among lineage identity, androgen receptor signaling, chromatin organization, metabolic adaptation, and therapy-induced plasticity. HOXB13 is a prostate-enriched homeobox transcription factor classically recognized for its roles in prostate development, androgen receptor transcriptional regulation, and hereditary prostate cancer susceptibility. However, emerging evidence indicates that HOXB13 functions beyond lineage specification. HOXB13 organizes prostate-specific transcriptional programs, shapes androgen receptor cistromes, regulates AR-variant activity in castration-resistant prostate cancer, and controls chromatin-dependent metabolic gene expression. Mechanistically, HOXB13 can recruit HDAC3 to suppress de novo lipogenesis, whereas HOXB13 loss or G84E mutation derepresses lipogenic enhancers, promotes lipid accumulation, enhances motility, and increases metastatic potential. In advanced disease, HOXB13 activity may be further reshaped by altered androgen receptor signaling, cofactor switching, mutation, and post-translational modifications, including acetylation and phosphorylation. These regulatory layers suggest that HOXB13 expression alone may be insufficient to define its function; rather, HOXB13 may exist in distinct functional states that influence AR/luminal identity, lipid metabolism, glycolytic-hypoxic adaptation, lineage plasticity, and therapeutic vulnerability. In this review, we discuss HOXB13 as a lineage-restricted chromatin-metabolic regulator in prostate cancer and highlight kinase-dependent regulation, as an emerging area for future investigation.

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