Interplay between sirtuins, MYC and hypoxia-inducible factor in cancer-associated metabolic reprogramming

Abstract

In the early twentieth century, Otto Heinrich Warburg described an elevated rate of glycolysis occurring in cancer cells, even in the presence of atmospheric oxygen (the Warburg effect). Despite the inefficiency of ATP generation through glycolysis, the breakdown of glucose into lactate provides cancer cells with a number of advantages, including the ability to withstand fluctuations in oxygen levels, and the production of intermediates that serve as building blocks to support rapid proliferation. Recent evidence from many cancer types supports the notion that pervasive metabolic reprogramming in cancer and stromal cells is a crucial feature of neoplastic transformation. Two key transcription factors that play major roles in this metabolic reprogramming are hypoxia inducible factor-1 (HIF1) and MYC. Sirtuin-family deacetylases regulate diverse biological processes, including many aspects of tumor biology. Recently, the sirtuin SIRT6 has been shown to inhibit the transcriptional output of both HIF1 and MYC, and to function as a tumor suppressor. In this Review, we highlight the importance of HIF1 and MYC in regulating tumor metabolism and their regulation by sirtuins, with a main focus on SIRT6.

Keywords: HIF; MYC; Metabolic reprogramming; Sirtuins; Warburg effect.

Fig. 1.

Dual roles for SIRT6 in cancer. SIRT6 has been reported to have both tumor suppressor and oncogenic properties. Reduced levels of SIRT6 have been described in colon cancer (CC), hepatocellular carcinoma (HCC), pancreatic cancer (PaC) and head and neck squamous cell carcinoma (HNSCC), correlating with increased cancer stage and grade, and/or with a shortened time to relapse in comparison to tumors with higher levels of SIRT6. SIRT6 can protect against tumorigenesis through multiple pathways: (1) inhibition of HIF-1α and MYC transcriptional activity, which decreases glycolysis and cellular proliferation, respectively; (2) inhibition of the anti-apoptotic factor survivin; (3) activation of the p53 and p73 apoptosis pathways in cancer cells specifically. Furthermore, SIRT6 represses SREBP1 and SREBP2 (SREBP1/2) and JUN activity, resulting in reduced lipogenesis and insulin–IGF-1-like signaling (IIS), respectively. Both of these processes likely impact cancer cell proliferation. By contrast, high SIRT6 levels have been reported in breast cancer (BC), PaC and prostate cancer (PrC), and are associated with drug resistance and poor prognosis. High SIRT6 levels promote cellular proliferation through deacetylation of the cell cycle control proteins FOXO3a and p53, and increase IL-8- and TNF-mediated inflammatory responses, angiogenesis and tumor metastasis in part through activation of the Ca²⁺ channel TRPM2. Ac, acetyl group; TNF, tumor necrosis factor; IL-8, interleukin-8.

Fig. 2.

SIRT6 as a master regulator of glucose metabolism. SIRT6 regulates glucose metabolism through at least three distinct mechanisms. SIRT6 deacetylates histone H3, thereby attenuating transcriptional output of (1) HIF-1α and (2) JUN, which normally enhance glucose uptake and induce glycolysis or activate the insulin–IGF-1-like signaling (IIS) pathway. (3) SIRT6 deacetylates the histone acetyltransferase GCN5 (KAT2A), which in turn acetylates and activates the transcriptional regulator PPARγ coactivator-1α (PGC-1α), reducing de novo production of glucose (gluconeogenesis) in the liver. Ac, acetyl group; HAT, histone acetyltransferase; H3, histone H3; TF, transcription factor.

Fig. 3.

Roles of sirtuins in regulating MYC- and HIF-mediated tumor metabolic reprogramming. Schematic overview of the known mechanisms through which the sirtuin proteins regulate the activity of HIF (A) and MYC (B) proteins. (A) SIRT1, SIRT3 and SIRT6 modulate HIF activity through deacetylation of histone (SIRT6) and non-histone (SIRT1/3) proteins. SIRT1 deacetylates HIF-1α directly. Leammle et al. (Leammle et al., 2012) showed that deacetylation of HIF-1α results in elevated transcription of HIF target genes (gray arrow), whereas Lim and colleagues (Lim et al., 2010) found that deacetylated HIF-1α inhibits the recruitment of p300 to the promoters of HIF-1α target genes (blue inhibitory T bar). In addition, SIRT7 also inhibits HIF activity; however, the underlying mechanism is unknown. (B) SIRT1, SIRT2, SIRT4, SIRT6 and SIRT7 all regulate MYC activity, either through deacetylation of histones (SIRT2/6/7) or of other proteins (SIRT1). SIRT4 regulates glutamine metabolism through effects on GDH, downstream of MYC. Ac, acetyl group; ADPr, ADP ribosyl group; MnSOD, manganese superoxide dismutase; IDH2, isocitrate dehydrogenase 2; ROS, reactive oxygen species; HIF, hypoxia inducible factor; NAD⁺, nicotinamide adenine dinucleotide; MKP3, MAP kinase phosphatase 3; GDH, glutamate dehydrogenase; H3K9, histone 3 lysine 9; H3K18, histone 3 lysine 18; H3K56, histone 3 lysine 56; H4K16, histone 4 lysine 16; NEDD4, neural precursor cell expressed developmentally downregulated protein 4.