Hypermethylated in cancer 1(HIC1) suppresses non-small cell lung cancer progression by targeting interleukin-6/Stat3 pathway.
Non-small cell lung cancer (NSCLC), which accounts for more than 80% of lung cancers, is a leading cause of cancer mortality worldwide. However, the mechanism underlying its progression remains unclear. Here we found that HIC1 promoter was heavily methylated in NSCLC cell lines and tissues contributing to its low expression compared to normal controls. Restoring HIC1 expression inhibited migration, invasion and promoted inducible apoptosis of NSCLC cells. Notably, HIC1 is a tumor suppressor through inhibiting the transcription of IL-6 by sequence-specific binding on its promoter. Restoring IL-6 expression could partially rescue these phenotypes induced by HIC1 in vitro and in vivo. Mechanistic analyses show that autocrine secretion of IL-6 induced by loss of HIC1 activated STAT3 through IL-6/JAK pathway and was associated with NSCLC progression. The HIC1/IL-6 axis may serve as a prognostic biomarker and provide an attractive therapeutic target for NSCLC.
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xiumin
X
Wang
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yingying
Y
Wang
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Gang
G
Xiao
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Jinglong
J
Wang
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Lidong
L
Zu
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Mingang
M
Hao
Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xueqing
X
Sun
Department of Chest Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yujie
Y
Fu
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Guohong
G
Hu
Cancer institute, Fudan University Shanghai Cancer Center, Shanghai, China.
Jianhua
J
Wang
D000072283:A549 Cells; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D019175:DNA Methylation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous
C499808:HIC1 protein, human; D015850:Interleukin-6; D051741:Kruppel-Like Transcription Factors; D050796:STAT3 Transcription Factor
HIC1/IL-6 axis; NSCLC; hypermethylation