Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

M. Björkman, Päivi Östling, Ville Härmä, J. Virtanen, John Mpindi, Juha K. Rantala, T. Mirtti, T. Vesterinen, M. Lundin, A. Sankila, A. Rannikko, E. Kaivanto, Pekka Kohonen, Olli Kallioniemi, Matthias Nees (Corresponding Author)

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Abstract

Our understanding of key epigenetic regulators involved in specific biological processes and cancers is still incomplete, despite great progress in genome-wide studies of the epigenome. Here, we carried out a systematic, genome-wide analysis of the functional significance of 615 epigenetic proteins in prostate cancer (PrCa) cells. We used the high-content cell-spot microarray technology and siRNA silencing of PrCa cell lines for functional screening of cell proliferation, survival, androgen receptor (AR) expression, histone methylation and acetylation. Our study highlights subsets of epigenetic enzymes influencing different cancer cell phenotypes. Plant homeo domain (PHD) finger proteins have a key role in cell survival and histone methylation, whereas histone deacetylases were primarily involved in regulating AR expression. In contrast, JumonjiC-domain (JmjC) containing histone lysine demethylases (KDMs) mainly had an impact on cell proliferation. Our results show that the KDMs JARID1B, PHF8, KDM3A, KDM3B and KDM4A were highly expressed in clinical PrCa samples. The PHD-finger protein 8 (PHF8), a transcriptional coactivator with both PHD- and JmjC-domains, was moderately to strongly expressed in 80% of clinical PrCa samples, whereas 76% of normal and benign samples were negative or only showed weak PHF8 expression. Strong PHF8 expression correlated significantly with high Gleason grade and was borderline significant for poor prognosis. The results of functional PHF8 knockdown implicate a role in cell migration and invasion, as shown by cell motility and 3-D invasion assays. Our study suggests that various cellular phenotypes are regulated by distinct subsets of epigenetic enzymes. Proteins interpreting and modifying histone methylation, such as JmjC-domain and particularly PHD-finger proteins like PHF8, are activated in subsets of PrCa's and promote cancer relevant phenotypes.
Original languageEnglish
Pages (from-to)3444-3456
JournalOncogene
Volume31
Issue number29
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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Histone Demethylases
Epigenomics
Fingers
Cell Movement
Prostatic Neoplasms
Cell Proliferation
Enzymes
Homeodomain Proteins
Plant Proteins
Proteins
Histones
Methylation
Androgen Receptors
Phenotype
Cell Survival
Genome
Biological Phenomena
Neoplasms
Histone Deacetylases
Acetylation

Cite this

Björkman, M. ; Östling, Päivi ; Härmä, Ville ; Virtanen, J. ; Mpindi, John ; Rantala, Juha K. ; Mirtti, T. ; Vesterinen, T. ; Lundin, M. ; Sankila, A. ; Rannikko, A. ; Kaivanto, E. ; Kohonen, Pekka ; Kallioniemi, Olli ; Nees, Matthias. / Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion. In: Oncogene. 2011 ; Vol. 31, No. 29. pp. 3444-3456.
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title = "Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion",
abstract = "Our understanding of key epigenetic regulators involved in specific biological processes and cancers is still incomplete, despite great progress in genome-wide studies of the epigenome. Here, we carried out a systematic, genome-wide analysis of the functional significance of 615 epigenetic proteins in prostate cancer (PrCa) cells. We used the high-content cell-spot microarray technology and siRNA silencing of PrCa cell lines for functional screening of cell proliferation, survival, androgen receptor (AR) expression, histone methylation and acetylation. Our study highlights subsets of epigenetic enzymes influencing different cancer cell phenotypes. Plant homeo domain (PHD) finger proteins have a key role in cell survival and histone methylation, whereas histone deacetylases were primarily involved in regulating AR expression. In contrast, JumonjiC-domain (JmjC) containing histone lysine demethylases (KDMs) mainly had an impact on cell proliferation. Our results show that the KDMs JARID1B, PHF8, KDM3A, KDM3B and KDM4A were highly expressed in clinical PrCa samples. The PHD-finger protein 8 (PHF8), a transcriptional coactivator with both PHD- and JmjC-domains, was moderately to strongly expressed in 80{\%} of clinical PrCa samples, whereas 76{\%} of normal and benign samples were negative or only showed weak PHF8 expression. Strong PHF8 expression correlated significantly with high Gleason grade and was borderline significant for poor prognosis. The results of functional PHF8 knockdown implicate a role in cell migration and invasion, as shown by cell motility and 3-D invasion assays. Our study suggests that various cellular phenotypes are regulated by distinct subsets of epigenetic enzymes. Proteins interpreting and modifying histone methylation, such as JmjC-domain and particularly PHD-finger proteins like PHF8, are activated in subsets of PrCa's and promote cancer relevant phenotypes.",
author = "M. Bj{\"o}rkman and P{\"a}ivi {\"O}stling and Ville H{\"a}rm{\"a} and J. Virtanen and John Mpindi and Rantala, {Juha K.} and T. Mirtti and T. Vesterinen and M. Lundin and A. Sankila and A. Rannikko and E. Kaivanto and Pekka Kohonen and Olli Kallioniemi and Matthias Nees",
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Björkman, M, Östling, P, Härmä, V, Virtanen, J, Mpindi, J, Rantala, JK, Mirtti, T, Vesterinen, T, Lundin, M, Sankila, A, Rannikko, A, Kaivanto, E, Kohonen, P, Kallioniemi, O & Nees, M 2011, 'Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion', Oncogene, vol. 31, no. 29, pp. 3444-3456. https://doi.org/10.1038/onc.2011.512

Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion. / Björkman, M.; Östling, Päivi; Härmä, Ville; Virtanen, J.; Mpindi, John; Rantala, Juha K.; Mirtti, T.; Vesterinen, T.; Lundin, M.; Sankila, A.; Rannikko, A.; Kaivanto, E.; Kohonen, Pekka; Kallioniemi, Olli; Nees, Matthias (Corresponding Author).

In: Oncogene, Vol. 31, No. 29, 2011, p. 3444-3456.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion

AU - Björkman, M.

AU - Östling, Päivi

AU - Härmä, Ville

AU - Virtanen, J.

AU - Mpindi, John

AU - Rantala, Juha K.

AU - Mirtti, T.

AU - Vesterinen, T.

AU - Lundin, M.

AU - Sankila, A.

AU - Rannikko, A.

AU - Kaivanto, E.

AU - Kohonen, Pekka

AU - Kallioniemi, Olli

AU - Nees, Matthias

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N2 - Our understanding of key epigenetic regulators involved in specific biological processes and cancers is still incomplete, despite great progress in genome-wide studies of the epigenome. Here, we carried out a systematic, genome-wide analysis of the functional significance of 615 epigenetic proteins in prostate cancer (PrCa) cells. We used the high-content cell-spot microarray technology and siRNA silencing of PrCa cell lines for functional screening of cell proliferation, survival, androgen receptor (AR) expression, histone methylation and acetylation. Our study highlights subsets of epigenetic enzymes influencing different cancer cell phenotypes. Plant homeo domain (PHD) finger proteins have a key role in cell survival and histone methylation, whereas histone deacetylases were primarily involved in regulating AR expression. In contrast, JumonjiC-domain (JmjC) containing histone lysine demethylases (KDMs) mainly had an impact on cell proliferation. Our results show that the KDMs JARID1B, PHF8, KDM3A, KDM3B and KDM4A were highly expressed in clinical PrCa samples. The PHD-finger protein 8 (PHF8), a transcriptional coactivator with both PHD- and JmjC-domains, was moderately to strongly expressed in 80% of clinical PrCa samples, whereas 76% of normal and benign samples were negative or only showed weak PHF8 expression. Strong PHF8 expression correlated significantly with high Gleason grade and was borderline significant for poor prognosis. The results of functional PHF8 knockdown implicate a role in cell migration and invasion, as shown by cell motility and 3-D invasion assays. Our study suggests that various cellular phenotypes are regulated by distinct subsets of epigenetic enzymes. Proteins interpreting and modifying histone methylation, such as JmjC-domain and particularly PHD-finger proteins like PHF8, are activated in subsets of PrCa's and promote cancer relevant phenotypes.

AB - Our understanding of key epigenetic regulators involved in specific biological processes and cancers is still incomplete, despite great progress in genome-wide studies of the epigenome. Here, we carried out a systematic, genome-wide analysis of the functional significance of 615 epigenetic proteins in prostate cancer (PrCa) cells. We used the high-content cell-spot microarray technology and siRNA silencing of PrCa cell lines for functional screening of cell proliferation, survival, androgen receptor (AR) expression, histone methylation and acetylation. Our study highlights subsets of epigenetic enzymes influencing different cancer cell phenotypes. Plant homeo domain (PHD) finger proteins have a key role in cell survival and histone methylation, whereas histone deacetylases were primarily involved in regulating AR expression. In contrast, JumonjiC-domain (JmjC) containing histone lysine demethylases (KDMs) mainly had an impact on cell proliferation. Our results show that the KDMs JARID1B, PHF8, KDM3A, KDM3B and KDM4A were highly expressed in clinical PrCa samples. The PHD-finger protein 8 (PHF8), a transcriptional coactivator with both PHD- and JmjC-domains, was moderately to strongly expressed in 80% of clinical PrCa samples, whereas 76% of normal and benign samples were negative or only showed weak PHF8 expression. Strong PHF8 expression correlated significantly with high Gleason grade and was borderline significant for poor prognosis. The results of functional PHF8 knockdown implicate a role in cell migration and invasion, as shown by cell motility and 3-D invasion assays. Our study suggests that various cellular phenotypes are regulated by distinct subsets of epigenetic enzymes. Proteins interpreting and modifying histone methylation, such as JmjC-domain and particularly PHD-finger proteins like PHF8, are activated in subsets of PrCa's and promote cancer relevant phenotypes.

U2 - 10.1038/onc.2011.512

DO - 10.1038/onc.2011.512

M3 - Article

VL - 31

SP - 3444

EP - 3456

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 29

ER -