Xiaoting Wang1,2, Chong Xu1,2, Shengming Wang1,2, Weijun Huang1,2, Yuenan Liu1,2, Xiaoxu Zhang1,2, Niannian Li1,2, Zhenfei Gao1,2, Fan Wang1,2, Nan Zhang3, Jian Guan1,2, Hongliang Yi4,5, Feng Liu6,7. 1. Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai JiaoTong University, Shanghai JiaoTong University Affiliated Sixth People's Hospital, 600 Yishan Road, Xuhui, 200233, Shanghai, China. 2. Shanghai Key Laboratory of Sleep Disordered Breathing, 600 Yishan Road, Xuhui, 200233, Shanghai, China. 3. Department of Oncology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250013, Shandong, China. 4. Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai JiaoTong University, Shanghai JiaoTong University Affiliated Sixth People's Hospital, 600 Yishan Road, Xuhui, 200233, Shanghai, China. yihongl@126.com. 5. Shanghai Key Laboratory of Sleep Disordered Breathing, 600 Yishan Road, Xuhui, 200233, Shanghai, China. yihongl@126.com. 6. Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai JiaoTong University, Shanghai JiaoTong University Affiliated Sixth People's Hospital, 600 Yishan Road, Xuhui, 200233, Shanghai, China. liufeng@sibs.ac.cn. 7. Shanghai Key Laboratory of Sleep Disordered Breathing, 600 Yishan Road, Xuhui, 200233, Shanghai, China. liufeng@sibs.ac.cn.
Abstract
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 αKG supplementation. By transcriptomic analysis, we identified CECR2, which encodes a histone acetyl-lysine reader, as the downstream target gene for Gln and αKG. 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 αKG supplementation could be magnified either, suggested that CECR2 feedback suppressed Gln and αKG'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-αKG-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.
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 αKG supplementation. By transcriptomic analysis, we identified CECR2, which encodes a histone acetyl-lysine reader, as the downstream target gene for Gln and αKG. 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 αKG supplementation could be magnified either, suggested that CECR2 feedback suppressed Gln and αKG'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-αKG-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.
Authors: Chendong Yang; Jessica Sudderth; Tuyen Dang; Robert M Bachoo; Robert G Bachoo; Jeffrey G McDonald; Ralph J DeBerardinis Journal: Cancer Res Date: 2009-10-13 Impact factor: 12.701