A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding

Qilai Huang; Thomas Whitington; Ping Gao; Johan F. Lindberg; Yuehong Yang; Jielin Sun; Marja-Riitta Väisänen; Robert Szulkin; Matti Annala; Jian Yan; Lars A. Egevad; Kai Zhang; Ruizhu Lin; Arttu Jolma; Matti Nykter; Aki Manninen; Fredrik Wiklund; Markku H. Vaarala; Tapio Visakorpi; Jianfeng Xu; Jussi Taipale; Gong-Hong Wei

doi:10.1038/ng.2862

A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding

Qilai Huang, Thomas Whitington, Ping Gao, Johan F. Lindberg, Yuehong Yang, Jielin Sun, Marja-Riitta Väisänen, Robert Szulkin, Matti Annala, Jian Yan, Lars A. Egevad, Kai Zhang, Ruizhu Lin, Arttu Jolma, Matti Nykter, Aki Manninen, Fredrik Wiklund, Markku H. Vaarala, Tapio Visakorpi, Jianfeng XuJussi Taipale^*, Gong-Hong Wei^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

173 Citations (Scopus)

Abstract

Genome-wide association studies have identified thousands of SNPs associated with predisposition to various diseases, including prostate cancer. However, the mechanistic roles of these SNPs remain poorly defined, particularly for noncoding polymorphisms. Here we find that the prostate cancer risk-associated SNP rs339331 at 6q22 lies within a functional HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of the rs339331-associated gene RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration and invasion. Clinical data indicate that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis and risk of biochemical relapse. Finally, we observe a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. Together, our results suggest that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13.

Original language	English
Pages (from-to)	126-135
Journal	Nature Genetics
Volume	46
Issue number	2
Online published	5 Jan 2014
DOIs	https://doi.org/10.1038/ng.2862
Publication status	Published - Feb 2014
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access Output

10.1038/ng.2862

Other Access Options

Check CityUHK Library

Permanent Link

Right click to copy link

Cite this

Huang, Q., Whitington, T., Gao, P., Lindberg, J. F., Yang, Y., Sun, J., Väisänen, M.-R., Szulkin, R., Annala, M., Yan, J., Egevad, L. A., Zhang, K., Lin, R., Jolma, A., Nykter, M., Manninen, A., Wiklund, F., Vaarala, M. H., Visakorpi, T., ... Wei, G.-H. (2014). A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nature Genetics, 46(2), 126-135. https://doi.org/10.1038/ng.2862

@article{223d8377ae924cfc871f8f6cec3cb838,

title = "A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding",

abstract = "Genome-wide association studies have identified thousands of SNPs associated with predisposition to various diseases, including prostate cancer. However, the mechanistic roles of these SNPs remain poorly defined, particularly for noncoding polymorphisms. Here we find that the prostate cancer risk-associated SNP rs339331 at 6q22 lies within a functional HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of the rs339331-associated gene RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration and invasion. Clinical data indicate that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis and risk of biochemical relapse. Finally, we observe a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. Together, our results suggest that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13. ",

author = "Qilai Huang and Thomas Whitington and Ping Gao and Lindberg, {Johan F.} and Yuehong Yang and Jielin Sun and Marja-Riitta V{\"a}is{\"a}nen and Robert Szulkin and Matti Annala and Jian Yan and Egevad, {Lars A.} and Kai Zhang and Ruizhu Lin and Arttu Jolma and Matti Nykter and Aki Manninen and Fredrik Wiklund and Vaarala, {Markku H.} and Tapio Visakorpi and Jianfeng Xu and Jussi Taipale and Gong-Hong Wei",

year = "2014",

month = feb,

doi = "10.1038/ng.2862",

language = "English",

volume = "46",

pages = "126--135",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

number = "2",

}

Huang, Q, Whitington, T, Gao, P, Lindberg, JF, Yang, Y, Sun, J, Väisänen, M-R, Szulkin, R, Annala, M, Yan, J, Egevad, LA, Zhang, K, Lin, R, Jolma, A, Nykter, M, Manninen, A, Wiklund, F, Vaarala, MH, Visakorpi, T, Xu, J, Taipale, J & Wei, G-H 2014, 'A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding', Nature Genetics, vol. 46, no. 2, pp. 126-135. https://doi.org/10.1038/ng.2862

TY - JOUR

T1 - A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding

AU - Huang, Qilai

AU - Whitington, Thomas

AU - Gao, Ping

AU - Lindberg, Johan F.

AU - Yang, Yuehong

AU - Sun, Jielin

AU - Väisänen, Marja-Riitta

AU - Szulkin, Robert

AU - Annala, Matti

AU - Yan, Jian

AU - Egevad, Lars A.

AU - Zhang, Kai

AU - Lin, Ruizhu

AU - Jolma, Arttu

AU - Nykter, Matti

AU - Manninen, Aki

AU - Wiklund, Fredrik

AU - Vaarala, Markku H.

AU - Visakorpi, Tapio

AU - Xu, Jianfeng

AU - Taipale, Jussi

AU - Wei, Gong-Hong

PY - 2014/2

Y1 - 2014/2

N2 - Genome-wide association studies have identified thousands of SNPs associated with predisposition to various diseases, including prostate cancer. However, the mechanistic roles of these SNPs remain poorly defined, particularly for noncoding polymorphisms. Here we find that the prostate cancer risk-associated SNP rs339331 at 6q22 lies within a functional HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of the rs339331-associated gene RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration and invasion. Clinical data indicate that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis and risk of biochemical relapse. Finally, we observe a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. Together, our results suggest that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13.

AB - Genome-wide association studies have identified thousands of SNPs associated with predisposition to various diseases, including prostate cancer. However, the mechanistic roles of these SNPs remain poorly defined, particularly for noncoding polymorphisms. Here we find that the prostate cancer risk-associated SNP rs339331 at 6q22 lies within a functional HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of the rs339331-associated gene RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration and invasion. Clinical data indicate that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis and risk of biochemical relapse. Finally, we observe a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. Together, our results suggest that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13.

UR - http://www.scopus.com/inward/record.url?scp=84895800675&partnerID=8YFLogxK

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-84895800675&origin=recordpage

U2 - 10.1038/ng.2862

DO - 10.1038/ng.2862

M3 - RGC 21 - Publication in refereed journal

C2 - 24390282

SN - 1061-4036

VL - 46

SP - 126

EP - 135

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding

Abstract

UN SDGs

Access Output

Other Access Options

Permanent Link

Other Files and Links

Fingerprint

Cite this