Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer

Yi Wen Huang, Joseph C. Liu, Daniel E. Deatherage, Jingqin Luo, David G. Mutch, Paul J. Goodfellow, David S. Miller, Tim H M Huang

Research output: Contribution to journalArticle

234 Citations (Scopus)

Abstract

Genetic amplification, mutation, and translocation are known to play a causal role in the upregulation of an oncogene in cancer cells. Here, we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the. SRY-related high mobility group box family, was found to be overexpressed (P < 0.005) in endometrial tumors (n = 74) compared with uninvolved controls (n = 20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared with the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P < 0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n = 6) and 68% of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacologic induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P < 0.001) and poor overall survival (P < 0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may upregulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA derepresses its oncogenic target in cancer cells.

Original languageEnglish (US)
Pages (from-to)9038-9046
Number of pages9
JournalCancer Research
Volume69
Issue number23
DOIs
StatePublished - Dec 1 2009

Fingerprint

Epigenetic Repression
Endometrial Neoplasms
MicroRNAs
Oncogenes
Neoplasms
Up-Regulation
Microsatellite Instability
CpG Islands
Acetylation
Endometrium
Epigenomics
Histones
Methylation
Transfection
Cell Proliferation
Cell Line
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Huang, Y. W., Liu, J. C., Deatherage, D. E., Luo, J., Mutch, D. G., Goodfellow, P. J., ... Huang, T. H. M. (2009). Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. Cancer Research, 69(23), 9038-9046. https://doi.org/10.1158/0008-5472.CAN-09-1499

Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. / Huang, Yi Wen; Liu, Joseph C.; Deatherage, Daniel E.; Luo, Jingqin; Mutch, David G.; Goodfellow, Paul J.; Miller, David S.; Huang, Tim H M.

In: Cancer Research, Vol. 69, No. 23, 01.12.2009, p. 9038-9046.

Research output: Contribution to journalArticle

Huang, YW, Liu, JC, Deatherage, DE, Luo, J, Mutch, DG, Goodfellow, PJ, Miller, DS & Huang, THM 2009, 'Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer', Cancer Research, vol. 69, no. 23, pp. 9038-9046. https://doi.org/10.1158/0008-5472.CAN-09-1499
Huang, Yi Wen ; Liu, Joseph C. ; Deatherage, Daniel E. ; Luo, Jingqin ; Mutch, David G. ; Goodfellow, Paul J. ; Miller, David S. ; Huang, Tim H M. / Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. In: Cancer Research. 2009 ; Vol. 69, No. 23. pp. 9038-9046.
@article{107dcebb08ee4115962c949303a110f1,
title = "Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer",
abstract = "Genetic amplification, mutation, and translocation are known to play a causal role in the upregulation of an oncogene in cancer cells. Here, we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the. SRY-related high mobility group box family, was found to be overexpressed (P < 0.005) in endometrial tumors (n = 74) compared with uninvolved controls (n = 20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared with the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P < 0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n = 6) and 68{\%} of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacologic induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P < 0.001) and poor overall survival (P < 0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may upregulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA derepresses its oncogenic target in cancer cells.",
author = "Huang, {Yi Wen} and Liu, {Joseph C.} and Deatherage, {Daniel E.} and Jingqin Luo and Mutch, {David G.} and Goodfellow, {Paul J.} and Miller, {David S.} and Huang, {Tim H M}",
year = "2009",
month = "12",
day = "1",
doi = "10.1158/0008-5472.CAN-09-1499",
language = "English (US)",
volume = "69",
pages = "9038--9046",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "23",

}

TY - JOUR

T1 - Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer

AU - Huang, Yi Wen

AU - Liu, Joseph C.

AU - Deatherage, Daniel E.

AU - Luo, Jingqin

AU - Mutch, David G.

AU - Goodfellow, Paul J.

AU - Miller, David S.

AU - Huang, Tim H M

PY - 2009/12/1

Y1 - 2009/12/1

N2 - Genetic amplification, mutation, and translocation are known to play a causal role in the upregulation of an oncogene in cancer cells. Here, we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the. SRY-related high mobility group box family, was found to be overexpressed (P < 0.005) in endometrial tumors (n = 74) compared with uninvolved controls (n = 20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared with the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P < 0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n = 6) and 68% of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacologic induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P < 0.001) and poor overall survival (P < 0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may upregulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA derepresses its oncogenic target in cancer cells.

AB - Genetic amplification, mutation, and translocation are known to play a causal role in the upregulation of an oncogene in cancer cells. Here, we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the. SRY-related high mobility group box family, was found to be overexpressed (P < 0.005) in endometrial tumors (n = 74) compared with uninvolved controls (n = 20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared with the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P < 0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n = 6) and 68% of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacologic induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P < 0.001) and poor overall survival (P < 0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may upregulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA derepresses its oncogenic target in cancer cells.

UR - http://www.scopus.com/inward/record.url?scp=71549121035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=71549121035&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-09-1499

DO - 10.1158/0008-5472.CAN-09-1499

M3 - Article

C2 - 19887623

AN - SCOPUS:71549121035

VL - 69

SP - 9038

EP - 9046

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 23

ER -