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Abstract
Diverse functions of SIRT1 regulated by DBC1 in cancer
Ja-Eun Kim
Department of Pharmacology, Kyung Hee University, School of Medicine
SIRT1, a protein deacetylase, participates in various cellular functions including gene
silencing, cell proliferation, apoptosis, metabolism and tumorigenesis. Whereas the
cellular functions of SIRT1 have been extensively investigated, less is known about the
regulation of SIRT1 activity. Here we show that Deleted in Breast Cancer-1 (DBC1)
directly
interacts
and
inhibits
SIRT1
deacetylase
activity
in vitro and in vivo.
Downregulation of DBC1 expression enhances the deacetylation of SIRT1-target proteins
such as p53 and FOXO, and thus potentiates SIRT1-dependent inhibition of apoptosis
induced by cellular stress, suggesting a possible role of DBC1 as a tumor suppressor. In
addition, we have shown the novel function of SIRT1 to guard the genomic integrity
although SIRT1 deacetylation target has not been identified in this pathway. In this context,
DBC1 localized in chromatin inhibits the SIRT1-dependent repair and plays a role as a
possible tumor promoter. Overall, DBC1 exerts opposite functions in the regulation of
tumorigenesis by inhibiting the deacetylase activity of SIRT1. Therefore, the interface
between DBC1 and SIRT1 would be a potential therapeutic target of cancer.