GYS1 induces glycogen accumulation and promotes tumor progression via the NF-κB pathway in Clear Cell Renal Carcinoma

Abstract

Metabolism reprogramming is a hallmark of many cancer types. We focused on clear cell renal carcinoma (ccRCC) which is characterized by its clear and glycogen-enriched cytoplasm with unknown reasons. The aim of this study was to identify the clinical significance, biological function, and molecular regulation of glycogen synthase 1 (GYS1) in ccRCC glycogen accumulation and tumor progression. Methods: We determined the clinical relevance of GYS1 and glycogen in ccRCC by immunohistochemistry and periodic acid-schiff staining in fresh tissue and by tissue micro-array. Metabolic profiling with GYS1 depletion was performed by metabolomics analysis. In vitro and xenograft mouse models were used to evaluate the impact of GYS1 on cell proliferation. High-throughput RNA-Seq analyses and co-immunoprecipitation-linked mass spectrometry were used to investigate the downstream targets of GYS1. Flow cytometry and CCK8 assays were performed to determine the effect of GYS1 and sunitinib on cell viability. Results: We observed that GYS1 was significantly overexpressed and glycogen was accumulated in ccRCC tissues. These effects were correlated with unfavorable patient survival. Silencing of GYS1 induced metabolomic perturbation manifested by a carbohydrate metabolism shift. Overexpression of GYS1 promoted tumor growth whereas its silencing suppressed it by activating the canonical NF-κB pathway. The indirect interaction between GYS1 and NF-κB was intermediated by RPS27A, which facilitated the phosphorylation and nuclear import of p65. Moreover, silencing of GYS1 increased the synthetic lethality of ccRCC cells to sunitinib treatment by concomitantly suppressing p65. Conclusions: Our study findings reveal an oncogenic role for GYS1 in cell proliferation and glycogen metabolism in ccRCC. Re-sensitization of ccRCC cells to sunitinib suggests that GYS1 is a useful indicator of unfavorable prognosis as well as a therapeutic target for patients with ccRCC.

DNA demethylase ALKBH1 promotes adipogenic differentiation via regulation of HIF-1 signaling

“…Glycogen synthase 1 (GYS1), downstream of HIF-1α, is the key enzyme functioning in the glycogen synthesis and significantly increases in the tumor microenvironment and hypoxic atmosphere ( 55 , 56 ). Accumulation of GYS1 in several types of cancer suppresses canonical nuclear factor κB (NF-κB) signaling ( 57 ) and AMP-activated protein kinase (AMPK) signaling to promote migration and proliferation of tumor cells ( 58 , 59 , 60 ). Aberrant expression of GYS1 is also related to the obesity phenotype in diabetes, but the mechanism remains unknown.…”

“…Accumulation of GYS1 in several types of cancer suppresses canonical nuclear factor κ B (NF-κ B) signaling [57] and AMP-activated protein kinase (AMPK) signaling to promote migration and proliferation of tumor cells [58][59][60]. Aberrant expression of GYS1 is also related to the obesity phenotype in diabetes, but the mechanism remains unknown.…”

Alternative splicing and alternative polyadenylation define tumor immune microenvironment and pharmacogenomic landscape in clear cell renal carcinoma

“…The behavior of ccRCC is to "clear the cytoplasm" due to its capacity to accumulate glycogen and lipids. 3 This malignancy is mostly asymptomatic in the early stage and diagnosed occasionally by imaging, with favorable clinical outcomes. Oppositely, in the late stage, the mortality of advanced patients is quite high owing to low sensitivity to radiotherapy and chemotherapy.…”

SPTBN1 inhibits inflammatory responses and hepatocarcinogenesis via the stabilization of SOCS1 and downregulation of p65 in hepatocellular carcinoma

“…The human NF-κB family consists of five DNA binding subunits, including p65/RelA, c-Rel, RelB, NF-κB1 (p50/p105) and NF-κB2 (p52/p100). These proteins function as heterodimeric or homodimeric transcription factors of various NF-κB proteins to control the transcription of genes containing a decameric cis-acting κB binding site 16 , 20 . Activation of the NF-κB signaling pathway is induced by proinflammatory cytokines, lipopolysaccharides, growth factors, and activation of antigen receptors, followed by phosphorylation and ubiquitin-mediated proteolysis of IκB proteins, which eventually lead to the translocation of NF-κB complexes into the nucleus to regulate gene expression.…”