A novel tumor suppressor CECR2 down regulation links glutamine metabolism contributes tumor growth in laryngeal squamous cell carcinoma
A novel tumor suppressor CECR2 down regulation links glutamine metabolism contributes tumor growth in laryngeal squamous cell carcinoma
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DOI：
10.1007/s12094-021-02603-y
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发表时间：
2021-04-07
影响因子：
3.4
通讯作者：
Liu, Feng
中科院分区：
文献类型：
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作者：
Wang, Xiaoting;Xu, Chong;Liu, Feng
目的谷氨酰胺在肿瘤代谢和进展中起重要作用。本研究旨在探讨Gln在喉鳞癌（LSCC）中的作用机制。方法采用CCK8和EdU法检测细胞增殖，采用线粒体应激法检测线粒体生物能活性。通过RNA测序和RT-qPCR验证基因表达谱。在LSCC患者中，通过免疫组化染色检测肿瘤及邻近组织中的蛋白表达并评分。通过稳定表达的shRNA在TU177细胞中进行RNAi。采用裸鼠致瘤性模型进行体内肿瘤生长分析。结果Gln剥夺抑制TU177细胞增殖，补充α - KG后恢复细胞增殖。通过转录组学分析，我们发现编码组蛋白乙酰赖氨酸解读器的CECR2是Gln和α KG的下游靶基因。在LSCC患者中，CECR2在肿瘤中的表达低于邻近组织。此外，CECR2缺失在体外和体内均能促进肿瘤细胞生长，提示其具有抑瘤作用。此外，CECR2的缺失可以恢复被Gln戒断抑制的细胞增殖，而补充α - KG促进的细胞增殖也可以被放大，说明CECR2反馈抑制了Gln和α - KG对肿瘤生长的作用。转录组学分析显示CECR2调节了一系列参与肿瘤进展的基因的表达。结论Gln-alpha KG-CECR2轴参与了LSCC的肿瘤生长。这一发现为使用相关代谢物作为LSCC的潜在治疗方法提供了潜在的治疗机会。
Purpose Glutamine plays an important role in tumor metabolism and progression. This research aimed to find out how Gln exert their effects on laryngeal squamous cell carcinoma (LSCC). Methods Cell proliferation was measured by CCK8 and EdU assay, mitochondrial bioenergetic activity was measured by mitochondrial stress tests. Gene expression profiling was revealed by RNA sequencing and validated by RT-qPCR. In LSCC patients, protein expression in tumor and adjacent tissues was examined and scored by IHC staining. RNAi was performed by stably expressed shRNA in TU177 cells. In vivo tumor growth analysis was performed using a nude mouse tumorigenicity model. Results Gln deprivation suppressed TU177 cell proliferation, which was restored by alpha KG supplementation. By transcriptomic analysis, we identified CECR2, which encodes a histone acetyl-lysine reader, as the downstream target gene for Gln and alpha KG. In LSCC patients, the expression of CECR2 in tumors was lower than adjacent tissues. Furthermore, deficiency of CECR2 promoted tumor cell growth both in vitro and in vivo, suggesting it has tumor suppressor effects. Besides, cell proliferation inhibited by Gln withdrawal could be restored by CECR2 depletion, and the proliferation boosted by alpha KG supplementation could be magnified either, suggested that CECR2 feedback suppressed Gln and alpha KG's effect on tumor growth. Transcriptomic profiling revealed CECR2 regulated the expression of a series of genes involved in tumor progression. Conclusion We confirmed the Gln-alpha KG-CECR2 axis contributes to tumor growth in LSCC. This finding provided a potential therapeutic opportunity for the use of associated metabolites as a potential treatment for LSCC.