GYS1 induces glycogen accumulation and promotes tumor progression via the NF-κB pathway in Clear Cell Renal Carcinoma
GYS1 induces glycogen accumulation and promotes tumor progression via the NF-κB pathway in Clear Cell Renal Carcinoma
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GYS1 在透明细胞肾癌中通过 NF-κB 途径诱导糖原积累并促进肿瘤进展
DOI：
10.7150/thno.46825
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Yun, Jing-ping
中科院分区：
文献类型：
--
作者：
Chen, Shi-lu;Huang, Qun-sheng;Yun, Jing-ping
代谢重编程是许多癌症类型的标志。我们专注于肾透明细胞癌（ccRCC），其特征在于其透明和糖原富集的细胞质，原因不明。本研究的目的是确定糖原合成酶1（GYS 1）在ccRCC糖原积累和肿瘤进展中的临床意义、生物学功能和分子调控。研究方法：我们通过新鲜组织中的免疫组织化学和过碘酸-希夫染色以及组织微阵列确定了ccRCC中GYS 1和糖原的临床相关性。通过代谢组学分析进行GYS 1耗竭的代谢谱分析。使用体外和异种移植小鼠模型来评估GYS 1对细胞增殖的影响。使用高通量RNA-Seq分析和免疫共沉淀连接质谱法来研究GYS 1的下游靶标。进行流式细胞术和CCK 8测定以确定GYS 1和舒尼替尼对细胞活力的影响。结果：我们观察到GYS 1在ccRCC组织中显著过表达，并且糖原在ccRCC组织中积累。这些影响与不利的患者生存相关。沉默GYS 1诱导代谢组学扰动表现为碳水化合物代谢的转变。GYS 1过表达促进肿瘤生长，而其沉默通过激活经典NF-κB通路抑制肿瘤生长。RPS 27 A介导GYS 1与NF-κB之间的间接相互作用，从而促进p65的磷酸化和核输入。此外，GYS 1的沉默通过伴随抑制p65而增加了ccRCC细胞对舒尼替尼处理的合成致死率。结论：我们的研究结果揭示了GYS 1在ccRCC细胞增殖和糖原代谢中的致癌作用。ccRCC细胞对舒尼替尼的再致敏表明GYS 1是不利预后的有用指标以及ccRCC患者的治疗靶点。
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.