Deleted in breast cancer-1 (DBC-1) in the interface between metabolism, aging and cancer

Abstract

DBC1 (deleted in breast cancer-1) is a nuclear protein that regulates cellular metabolism. Since alteration in cellular metabolism have been proposed to be the emerging 'hallmark' of cancer, it is possible that DBC1 may be implicated in the regulation of cancer cell energy metabolism. However, at this point any role of DBC1 in cancer is only speculative. In this review, we will discuss the new developments in DBC1 research, its molecular structure, regulatory roles and implication in metabolism, aging and cancer.

Figure 1. DBC1 a regulator of epigenetic modifiers and nuclear receptors

DBC1 binds and regulates the function of several nuclear proteins and epigenetic modifiers such as nuclear receptors (e.g. AR, RAR and Rev-Erbα receptor), HDACs (SIRT1 and HDAC3), the methyltransferase SUV39H1.

Figure 2. Functional structure of DBC1

The Figure describes the domains of DBC1 and its probable functions. Abbreviations N, N-terminus; C, C-terminus; NLS, nuclear localization sequence; LZ, leucine zipper; nudix, Nucleoside Diphosphate linked to X; EF-hand, (where EF stands for the E and F alpha helices of parvalbumin) are Ca²⁺-binding domains present in different Ca²⁺-binding proteins); CC, coiled coil.

Figure 3. Regulation of liver metabolism by DBC1

We have shown that DBC1 plays a crucial role in the development of liver steatosis by direct binding and inhibiting SIRT1, with the subsequent modulation of downstream effects of SIRT1 on hepatic lipogenesis and β-oxidation via AMPK [4]. It is likely that knockout of DBC1 decreases fatty liver infiltration by inducing SIRT1/LKB1-dependent activation of AMPK. AMPK phosphorylates and inactivates ACC. Inactivation of ACC leads to subsequent decrease in malonyl-CoA. This decrease in malonyl-CoA levels increases hepatic β-oxidation and reduced lipogenesis, preventing the development of liver steatosis.

Figure 4. Regulation of the SIRT1–DBC1 interaction by signalling pathways

The SIRT1–DBC1 interaction is regulated by metabolic inputs and also by the cAMP–PKA, the AMPK and the ATM/ATR pathways.