A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylation on Histone H3 during Androgen Signaling and in Prostate Cancer

Ji Young Kim; Taraswi Banerjee; Aurimas Vinckevicius; Qianyi Luo; J. Brandon Parker; Mairead R. Baker; Ishwar Radhakrishnan; Jian Jun Wei; Grant D. Barish; Debabrata Chakravarti

doi:10.1016/j.molcel.2014.03.043

A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylation on Histone H3 during Androgen Signaling and in Prostate Cancer

Ji Young Kim, Taraswi Banerjee, Aurimas Vinckevicius, Qianyi Luo, J. Brandon Parker, Mairead R. Baker, Ishwar Radhakrishnan, Jian Jun Wei, Grant D. Barish, Debabrata Chakravarti^*

^*Corresponding author for this work

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

97 Scopus citations

Abstract

Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target gene activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P, and this interaction facilitates the recruitment of the MLL1 complex and subsequent H3K4 tri-methylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a 6-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knockdown or chemical inhibition severely blocks WDR5 chromatin association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and as a major driver of androgen-dependent prostate cancer cell proliferation.

Original language	English (US)
Pages (from-to)	613-625
Number of pages	13
Journal	Molecular cell
Volume	54
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2014.03.043
State	Published - May 22 2014

Funding

We thank Winship Herr for generously providing a rabbit polyclonal WDR5 antibody. Work in the D.C laboratory is supported in part by NIH RO1 CA133755, PO1 HD 57877, and institutional (Robert H. Lurie Comprehensive Cancer Center and NU) grants and support. We gratefully acknowledge the help and support from the Northwestern University Next Generation Sequencing (NGS) Core Facility. We thank Ms. Nandini Chattopadhyay for technical assistance. The authors declare no conflicts of interests.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

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

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10.1016/j.molcel.2014.03.043

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Kim, J. Y., Banerjee, T., Vinckevicius, A., Luo, Q., Parker, J. B., Baker, M. R., Radhakrishnan, I., Wei, J. J., Barish, G. D., & Chakravarti, D. (2014). A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylation on Histone H3 during Androgen Signaling and in Prostate Cancer. Molecular cell, 54(4), 613-625. https://doi.org/10.1016/j.molcel.2014.03.043

@article{e87f803f4a61411fa3a32019460e6945,

title = "A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylation on Histone H3 during Androgen Signaling and in Prostate Cancer",

abstract = "Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target gene activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P, and this interaction facilitates the recruitment of the MLL1 complex and subsequent H3K4 tri-methylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a 6-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knockdown or chemical inhibition severely blocks WDR5 chromatin association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and as a major driver of androgen-dependent prostate cancer cell proliferation.",

author = "Kim, {Ji Young} and Taraswi Banerjee and Aurimas Vinckevicius and Qianyi Luo and Parker, {J. Brandon} and Baker, {Mairead R.} and Ishwar Radhakrishnan and Wei, {Jian Jun} and Barish, {Grant D.} and Debabrata Chakravarti",

note = "Funding Information: We thank Winship Herr for generously providing a rabbit polyclonal WDR5 antibody. Work in the D.C laboratory is supported in part by NIH RO1 CA133755, PO1 HD 57877, and institutional (Robert H. Lurie Comprehensive Cancer Center and NU) grants and support. We gratefully acknowledge the help and support from the Northwestern University Next Generation Sequencing (NGS) Core Facility. We thank Ms. Nandini Chattopadhyay for technical assistance. The authors declare no conflicts of interests. ",

year = "2014",

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Kim, JY, Banerjee, T, Vinckevicius, A, Luo, Q, Parker, JB, Baker, MR, Radhakrishnan, I , Wei, JJ , Barish, GD & Chakravarti, D 2014, 'A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylation on Histone H3 during Androgen Signaling and in Prostate Cancer', Molecular cell, vol. 54, no. 4, pp. 613-625. https://doi.org/10.1016/j.molcel.2014.03.043

TY - JOUR

T1 - A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylation on Histone H3 during Androgen Signaling and in Prostate Cancer

AU - Kim, Ji Young

AU - Banerjee, Taraswi

AU - Vinckevicius, Aurimas

AU - Luo, Qianyi

AU - Parker, J. Brandon

AU - Baker, Mairead R.

AU - Radhakrishnan, Ishwar

AU - Wei, Jian Jun

AU - Barish, Grant D.

AU - Chakravarti, Debabrata

N1 - Funding Information: We thank Winship Herr for generously providing a rabbit polyclonal WDR5 antibody. Work in the D.C laboratory is supported in part by NIH RO1 CA133755, PO1 HD 57877, and institutional (Robert H. Lurie Comprehensive Cancer Center and NU) grants and support. We gratefully acknowledge the help and support from the Northwestern University Next Generation Sequencing (NGS) Core Facility. We thank Ms. Nandini Chattopadhyay for technical assistance. The authors declare no conflicts of interests.

PY - 2014/5/22

Y1 - 2014/5/22

N2 - Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target gene activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P, and this interaction facilitates the recruitment of the MLL1 complex and subsequent H3K4 tri-methylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a 6-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knockdown or chemical inhibition severely blocks WDR5 chromatin association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and as a major driver of androgen-dependent prostate cancer cell proliferation.

AB - Upon androgen stimulation, PKN1-mediated histone H3 threonine 11 phosphorylation (H3T11P) promotes AR target gene activation. However, the underlying mechanism is not completely understood. Here, we show that WDR5, a subunit of the SET1/MLL complex, interacts with H3T11P, and this interaction facilitates the recruitment of the MLL1 complex and subsequent H3K4 tri-methylation (H3K4me3). Using ChIP-seq, we find that androgen stimulation results in a 6-fold increase in the number of H3T11P-marked regions and induces WDR5 colocalization to one third of H3T11P-enriched promoters, thus establishing a genome-wide relationship between H3T11P and recruitment of WDR5. Accordingly, PKN1 knockdown or chemical inhibition severely blocks WDR5 chromatin association and H3K4me3 on AR target genes. Finally, WDR5 is critical in prostate cancer cell proliferation and is hyperexpressed in human prostate cancers. Together, these results identify WDR5 as a critical epigenomic integrator of histone phosphorylation and methylation and as a major driver of androgen-dependent prostate cancer cell proliferation.

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A Role for WDR5 in Integrating Threonine 11 Phosphorylation to Lysine 4 Methylation on Histone H3 during Androgen Signaling and in Prostate Cancer

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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