β-hydroxybutyrate impairs nasopharyngeal carcinoma cell aggressiveness via histone deacetylase 4 inhibition.

Background: Cancer stem cell phenotype confers tumor aggressiveness in multiple malignancies, including nasopharyngeal carcinoma (NPC). Many studies supported that β-hydroxybutyrate (BHB), a ketone body, acts as an epigenetic factor with an anticancer effect. Nevertheless, the effects of BHB on NPC remain elusive. Objective: This study explored whether BHB suppressed the aggressive phenotype of NPC cells by suppressing their stemness-like characteristics and exerting an anti-NPC effect. Results: The proliferation, migration, and invasion abilities of NPC cells after BHB intervention were attenuated, the protein levels of E-cadherin were downregulated, that of N-cadherin and vimentin were upregulated, the volume and number of cell spheres were reduced, and the number of CD44 + cells (cell surface stem cell marker) was reduced. Knockdown of HDAC4 abrogated the effects of BHB on cell proliferation, invasive phenotype, and stemness. The molecular docking map of BHB-HDAC4 displayed that BHB binds the catalytic domain in HDAC4, speculating that BHB functions as an HDAC4-specific inhibitor, preventing the catalytic function of HDAC4 protein rather than inhibiting the translational synthesis of HDAC4 protein. Conclusions: BHB inhibited NPC cells' proliferation, stemness characteristics, and invasive phenotypes by specifically restraining HDAC4 expression. [ABSTRACT FROM AUTHOR]