Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma

Guang-Yuh Chiou; Chian Shiu Chien; Mong Lien Wang; Ming Teh Chen; Yi Ping Yang; Yung Luen Yu; Yueh Chien; Yun Ching Chang; Chiung Chyi Shen; Chung Ching Chio; Kai Hsi Lu; Hsin I. Ma; Kuan Hsuan Chen; Dean-Mo Liu; Stephanie A. Miller; Yi Wei Chen; Pin I. Huang; Yang Hsin Shih; Mien Chie Hung; Shih Hwa Chiou

doi:10.1016/j.molcel.2013.11.009

Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma

Guang-Yuh Chiou, Chian Shiu Chien, Mong Lien Wang, Ming Teh Chen, Yi Ping Yang, Yung Luen Yu, Yueh Chien, Yun Ching Chang, Chiung Chyi Shen, Chung Ching Chio, Kai Hsi Lu, Hsin I. Ma, Kuan Hsuan Chen, Dean-Mo Liu, Stephanie A. Miller, Yi Wei Chen, Pin I. Huang, Yang Hsin Shih, Mien Chie Hung^*, Shih Hwa Chiou

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

81 Scopus citations

Abstract

Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.

Original language	English
Pages (from-to)	693-706
Number of pages	14
Journal	Molecular Cell
Volume	52
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2013.11.009
State	Published - 12 Dec 2013

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Chiou, G.-Y., Chien, C. S., Wang, M. L., Chen, M. T., Yang, Y. P., Yu, Y. L., Chien, Y., Chang, Y. C., Shen, C. C., Chio, C. C., Lu, K. H., Ma, H. I., Chen, K. H., Liu, D.-M., Miller, S. A., Chen, Y. W., Huang, P. I., Shih, Y. H., Hung, M. C., & Chiou, S. H. (2013). Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma. Molecular Cell, 52(5), 693-706. https://doi.org/10.1016/j.molcel.2013.11.009

@article{a76cf5f741414011aeecb6eebc10d49c,

title = "Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma",

abstract = "Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.",

author = "Guang-Yuh Chiou and Chien, {Chian Shiu} and Wang, {Mong Lien} and Chen, {Ming Teh} and Yang, {Yi Ping} and Yu, {Yung Luen} and Yueh Chien and Chang, {Yun Ching} and Shen, {Chiung Chyi} and Chio, {Chung Ching} and Lu, {Kai Hsi} and Ma, {Hsin I.} and Chen, {Kuan Hsuan} and Dean-Mo Liu and Miller, {Stephanie A.} and Chen, {Yi Wei} and Huang, {Pin I.} and Shih, {Yang Hsin} and Hung, {Mien Chie} and Chiou, {Shih Hwa}",

year = "2013",

month = dec,

day = "12",

doi = "10.1016/j.molcel.2013.11.009",

language = "English",

volume = "52",

pages = "693--706",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "5",

}

Chiou, G-Y, Chien, CS, Wang, ML, Chen, MT, Yang, YP, Yu, YL, Chien, Y, Chang, YC, Shen, CC, Chio, CC, Lu, KH, Ma, HI, Chen, KH, Liu, D-M, Miller, SA, Chen, YW, Huang, PI, Shih, YH, Hung, MC & Chiou, SH 2013, 'Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma', Molecular Cell, vol. 52, no. 5, pp. 693-706. https://doi.org/10.1016/j.molcel.2013.11.009

TY - JOUR

T1 - Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma

AU - Chiou, Guang-Yuh

AU - Chien, Chian Shiu

AU - Wang, Mong Lien

AU - Chen, Ming Teh

AU - Yang, Yi Ping

AU - Yu, Yung Luen

AU - Chien, Yueh

AU - Chang, Yun Ching

AU - Shen, Chiung Chyi

AU - Chio, Chung Ching

AU - Lu, Kai Hsi

AU - Ma, Hsin I.

AU - Chen, Kuan Hsuan

AU - Liu, Dean-Mo

AU - Miller, Stephanie A.

AU - Chen, Yi Wei

AU - Huang, Pin I.

AU - Shih, Yang Hsin

AU - Hung, Mien Chie

AU - Chiou, Shih Hwa

PY - 2013/12/12

Y1 - 2013/12/12

N2 - Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.

AB - Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.

UR - http://www.scopus.com/inward/record.url?scp=84890226018&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2013.11.009

DO - 10.1016/j.molcel.2013.11.009

M3 - Article

C2 - 24332177

AN - SCOPUS:84890226018

SN - 1097-2765

VL - 52

SP - 693

EP - 706

JO - Molecular Cell

JF - Molecular Cell

IS - 5

ER -

Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma

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