Journal
NATURE METABOLISM
Volume 3, Issue 3, Pages 327-U47Publisher
NATURE RESEARCH
DOI: 10.1038/s42255-021-00367-x
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Funding
- NCI NIH HHS [R35 CA220483, P01 CA104838, F31 CA239514] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007229] Funding Source: Medline
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The accumulation of glycogen is a consistent feature of clear cell renal cell carcinoma (ccRCC). However, it has been found that glycogen is not essential for tumor cell proliferation and survival in ccRCC, both in vivo and in vitro. This suggests that glycogen build-up in ccRCC tumor cells may be a secondary and seemingly non-essential consequence of HIF-1 alpha signaling.
Glycogen accumulation is a highly consistent, distinguishable characteristic of clear cell renal cell carcinoma (ccRCC)(1). While elevated glycogen pools might be advantageous for ccRCC cells in nutrient-deprived microenvironments to sustain tumour viability, data supporting a biological role for glycogen in ccRCC are lacking. Here, we demonstrate that glycogen metabolism is not required for ccRCC proliferation in vitro nor xenograft tumour growth in vivo. Disruption of glycogen synthesis by CRISPR-mediated knockout of glycogen synthase 1 (GYS1) has no effect on proliferation in multiple cell lines, regardless of glucose concentrations or oxygen levels. Similarly, prevention of glycogen breakdown by deletion or pharmacological inhibition of glycogen phosphorylase B (PYGB) and L (PYGL) has no impact on cell viability under any condition tested. Lastly, in vivo xenograft experiments using the ccRCC cell line, UMRC2, reveal no substantial changes in tumour size or volume when glycogen metabolism is altered, largely mimicking the phenotype of our in vitro observations. Our findings suggest that glycogen build-up in established ccRCC tumour cells is likely to be a secondary, and apparently dispensable, consequence of constitutively active hypoxia-inducible factor 1-alpha (HIF-1 alpha) signalling. Glycogen accumulation is a hallmark of clear cell renal cell carcinoma. Xie et al. uncover that under metabolic stress or hypoxia, these glycogen deposits are dispensable for tumour cell proliferation and survival, both in vivo and in vitro.
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