Metabolic alteration in tumorigenesis

Abstract

Altered metabolism in cancer was first discovered by Otto Warburg early last century. Although the Warburg Effect has been widely used in tumor detection, relatively little progress had been made in mechanistic understanding of cancer metabolism in the subsequent eight decades. Genetic studies have recently identified mutations in human cancer targeting multiple enzymes involved in intermediate metabolism. One emerging mechanism common to these mutant enzymes is the accumulation of a metabolite that alters the epigenetic control. Otto Warburg [1,2] first discovered that cancer cells displayed enhanced glucose uptake and aerobic glycolysis, a phenomenon often referred as the Warburg Effect nowadays. Although the mechanism underlying the Warburg Effect is still not fully understood, increased uptake of glucose provides the basis to exploit its clinical application by 18 F-deoxyglucose positron emission tomography (PET) for tumor detection [3,4]. Decades after the Warburg Effect was discovered, the mechanistic insights of how metabolic alterations contribute to tumorigenesis are just emerging. Recent studies have revealed that eight metabolic genes, FH, SDHA, SDHB, SDHC, SDHD, SDHAF2, IDH1 and IDH2, encoding for subunits of four different metabolic enzymes, fumarate hydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), were mutated in a number of human cancers [5]. These findings provide compelling genetic evidence supporting the notion that altered metabolism contributes to, as opposed to the consequence of, tumorigenesis. Here, we first briefly discuss how metabolism is reprogrammed to support cancer cell proliferation. We then focus on one emerging mechanism that is common to the mutations targeting all four metabolic enzymes in accumulating a metabolite to alter the epigenetic modifications in human cancer.

Cbx4 Governs HIF-1α to Potentiate Angiogenesis of Hepatocellular Carcinoma by Its SUMO E3 Ligase Activity

“…To address whether Cbx proteins affect VEGF expression, we ectopically expressed several Flag-tagged members of Cbx family and Bmi1, another component of PRC1, into HCC cell line SMMC-7721 cells ( Figure 1A) but found that none of these affected the VEGF expression under normoxia (Figures 1B and 1C). Hypoxia is well documented to be implicated in the pathogenesis of a broad range of hepatic diseases, including HCC, and is one of the critical in vivo microenvironmental factors of cancers (Hanahan and Weinberg, 2011;Kang and Pantel, 2013;Rosmorduc and Housset, 2010;Yang et al, 2013). Intriguingly, overexpression of Cbx4, but not of other Cbx members or Bmi1, significantly increased VEGF expression under hypoxia (1% oxygen) in several HCC cell lines (Figures 1B and 1C;Figures S1A-S1C available online).…”

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

“…In addition to VHL, murine double minute 2 [30] and Jab1 [31] have also been reported to affect the ubiquitination and stability of HIF-1. It should be pointed out that the protein stability and transcriptional activity of HIF-1 can be regulated by several other factors besides hypoxia, such as the accumulation of intermediate metabolites, the loss of tumor-suppressor function and the gain of oncogene function [32].…”

Chromobox Homolog 4 is Positively Correlated to Tumor Growth, Survival and Activation of HIF-1α Signaling in Human Osteosarcoma under Normoxic Condition

“…Generally, HIF-1α pathway was activated by O 2 -dependent post-translational modification of prolyl hydroxylation 22 . However, the HIF-1α pathway is also regulated by other signals under normoxic conditions, such as the loss of tumor-suppressor function and the gain of oncogene function 23 , 24 .…”