Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase.
Chromatin modification is pivotal to the epithelial-mesenchymal transition (EMT), which confers potent metastatic potential to cancer cells. Here, we report a role for the chromatin remodeling factor lymphoid-specific helicase (LSH) in nasopharyngeal carcinoma (NPC), a prevalent cancer in China. LSH expression was increased in NPC, where it was controlled by the Epstein-Barr virus-encoded protein LMP1. In NPC cells in vitro and in vivo, LSH promoted cancer progression in part by regulating expression of fumarate hydratase (FH), a core component of the tricarboxylic acid cycle. LSH bound to the FH promoter, recruiting the epigenetic silencer factor G9a to repress FH transcription. Clinically, we found that the concentration of TCA intermediates in NPC patient sera was deregulated in the presence of LSH. RNAi-mediated silencing of FH mimicked LSH overexpression, establishing FH as downstream mediator of LSH effects. The TCA intermediates α-KG and citrate potentiated the malignant character of NPC cells, in part by altering IKKα-dependent EMT gene expression. In this manner, LSH furthered malignant progression of NPC by modifying cancer cell metabolism to support EMT. Cancer Res; 76(19); 5743-55. ©2016 AACR.
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China. Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, China.
Xiaozhen
X
He
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China. Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, China.
Bin
B
Yan
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Shuang
S
Liu
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China.
Jiantao
J
Jia
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China.
Weiwei
W
Lai
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China. Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, China.
Xing
X
Xin
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Can-E
CE
Tang
National and Local Joint Engineering Laboratory of High-throughput Molecular Diagnosis Technology, Translational Medicine Institute, The First People's Hospital of Chenzhou, University of South China, Chenzhou, Hunan, China.
Dixian
D
Luo
National and Local Joint Engineering Laboratory of High-throughput Molecular Diagnosis Technology, Translational Medicine Institute, The First People's Hospital of Chenzhou, University of South China, Chenzhou, Hunan, China.
Tan
T
Tan
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China.
Yiqun
Y
Jiang
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China. Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, China.
Ying
Y
Shi
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China. Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, China.
Yating
Y
Liu
Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Desheng
D
Xiao
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China. Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, China.
Ling
L
Chen
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Shao
S
Liu
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China.
Chao
C
Mao
Department of Pathology, School of Basic Medicine, Central South University, Hunan, China.
Gang
G
Yin
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
Yan
Y
Cheng
Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai, China. Institute of Biomedical Sciences, Fudan University, Shanghai, China.
Jia
J
Fan
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China. Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, China.
Ya
Y
Cao
Mouse Cancer Genetics Program, National Cancer Institute, Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Kathrin
K
Muegge
Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan, China. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, China. Key Laboratory of Carcinogenesis and Cancer Invasion (Central South University), Ministry of Education, Hunan, China. Key Laboratory of Carcinogenesis (Central South University), Ministry of Health, Hunan, China. taoyong@csu.edu.cn.
Yongguang
Y
Tao
D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000209:etiology*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D019343:Citric Acid / Q000494:pharmacology; D002952:Citric Acid Cycle; D004265:DNA Helicases / Q000502:physiology*; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005649:Fumarate Hydratase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007656:Ketoglutaric Acids / Q000494:pharmacology; D051379:Mice; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000209:etiology*; D062826:Zonula Occludens-1 Protein / Q000032:analysis
D007656:Ketoglutaric Acids; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D019343:Citric Acid; D004265:DNA Helicases; D005649:Fumarate Hydratase; C412063:HELLS protein, human