Depsipeptide, a novel inhibitor of histone deacetylase, suppresses the expression of various genes related to thyroid cancer at the level of transcription, US study findings indicate.
Jimin Xu and Jerome Hershman, both from David Geffen School of Medicine in Los Angeles, California, investigated the response of the nicotinamide N-methyltransferase (NNMT) gene to depsipeptide in a human papillary thyroid cancer cell line.
"Depsipeptide is a natural bicyclic peptide with potent anticancer activity that induces cell differentiation and apoptosis," write Xu and Hershman in the journal Thyroid.
Their experiments showed that depsipeptide reduced NNMT mRNA, protein, and catalytic activity in a dose- and time-dependent manner. By contrast, expression of the sodium iodide symporter was enhanced in treated cells.
In an attempt to elucidate the underlying mechanisms, the team next studied the effect of depsipeptide on NNMT promoter activity; this was significantly reduced in cancer cells expressing hepatocyte nuclear factor (HNF)-1β, but not in HNF-1β-negative cells.
Finally, they showed that depsipeptide depleted HNF-1β mRNA and protein and abolished DNA binding to the HNF-1 site in the NNMT promoter region, whereas the protein synthesis inhibitor cycloheximide and proteasome inhibitor MG-132 enhanced HNF-1β stability in depsipeptide-treated cells.
"The repression of NNMT is at least partially due to depletion of HNF-1β protein in the nuclei and loss of HNF-1β transactivation activity," the team concludes.
"The results of this study reveal a novel pathway for NNMT and HNF-1β regulation in some papillary thyroid cancer cells."