Posttranslational regulation of PGC-1α and its implication in cancer metabolism

Abstract

Deregulation of cellular metabolism is well established in cancer. The mitochondria are dynamic organelles and act as the center stage for energy metabolism. Central to mitochondrial regulatory network is peroxisome proliferator-activated receptor γ coactivator 1a (PGC-1α), which serves as a master regulator of mitochondrial proliferation and metabolism. The activity and stability of PGC-1α are subject to dynamic and versatile posttranslational modifications including phosphorylation, ubiquitination, methylation and acetylation in response to metabolic stress and other environmental signals. In this review, we describe the structure of PGC-1α. Then, we discuss recent advances in the posttranslational regulatory machinery of PGC-1α, which affects its transcriptional activity, stability and organelle localization. Furthermore, we address the important roles of PGC-1α in tumorigenesis and malignancy. Finally, we also mention the clinical therapeutic potentials of PGC-1α modulators. A better understanding of the elegant function of PGC-1α in cancer progression could provide novel insights into therapeutic interventions through the targeting of PGC-1α signaling.

Keywords: PGC-1α; cancer metabolism; posttranslational modifications.

Figure 1

Schematic domain structure of PGC‐1 family and isoforms. Sequence homology of the transcriptional coactivator PGC‐1 family members, including PGC‐1α, PGC‐1β, PRC and a short isoform, NT‐PGC‐1α. PGC‐1β shares sequence identity with PGC‐1α in AD (40%) and RRM (48%), respectively. As to PRC, the homology of each domain is 28 and 44%. As to NT‐PGC‐1α, the homology of AD domain with PGC‐1α is 100%. For each domain structure, the left corresponds to the N‐terminal of a protein, and the right to the C‐terminal. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Posttranslational modifications of PGC‐1α. The mainly identified sites for posttranslational modifications, including phosphorylation, acetylation, methylation and ubiquitination of PGC‐1α or NT‐PGC‐1α, are mapped in the protein structure. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Role of PGC‐1α in the regulation of cancer metabolism. The main altered metabolic pathways regulated by PGC‐1α and accounted for its pro‐ and anti‐neoplastic aspects in cancer cells. [Color figure can be viewed at wileyonlinelibrary.com]