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Article ; Online: Complete loss of H3K9 methylation dissolves mouse heterochromatin organization.

Montavon, Thomas / Shukeir, Nicholas / Erikson, Galina / Engist, Bettina / Onishi-Seebacher, Megumi / Ryan, Devon / Musa, Yaarub / Mittler, Gerhard / Meyer, Alexandra Graff / Genoud, Christel / Jenuwein, Thomas

Nature communications

2021 Volume 12, Issue 1, Page(s) 4359

Abstract: Histone H3 lysine 9 (H3K9) methylation is a central epigenetic modification that defines heterochromatin from unicellular to multicellular organisms. In mammalian cells, H3K9 methylation can be catalyzed by at least six distinct SET domain enzymes: ... ...

Abstract	Histone H3 lysine 9 (H3K9) methylation is a central epigenetic modification that defines heterochromatin from unicellular to multicellular organisms. In mammalian cells, H3K9 methylation can be catalyzed by at least six distinct SET domain enzymes: Suv39h1/Suv39h2, Eset1/Eset2 and G9a/Glp. We used mouse embryonic fibroblasts (MEFs) with a conditional mutation for Eset1 and introduced progressive deletions for the other SET domain genes by CRISPR/Cas9 technology. Compound mutant MEFs for all six SET domain lysine methyltransferase (KMT) genes lack all H3K9 methylation states, derepress nearly all families of repeat elements and display genomic instabilities. Strikingly, the 6KO H3K9 KMT MEF cells no longer maintain heterochromatin organization and have lost electron-dense heterochromatin. This is a compelling analysis of H3K9 methylation-deficient mammalian chromatin and reveals a definitive function for H3K9 methylation in protecting heterochromatin organization and genome integrity.
MeSH term(s)	Animals ; CRISPR-Cas Systems ; Chromatin Immunoprecipitation Sequencing ; Chromatography, Liquid ; Demethylation ; Epigenesis, Genetic ; Fibroblasts/enzymology ; Fibroblasts/metabolism ; Gene Deletion ; Heterochromatin/enzymology ; Heterochromatin/genetics ; Heterochromatin/metabolism ; Heterochromatin/ultrastructure ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/metabolism ; In Situ Hybridization, Fluorescence ; Lysine/metabolism ; Mass Spectrometry ; Methylation ; Mice ; Microscopy, Electron, Transmission ; Mutation ; Protein Processing, Post-Translational/genetics ; RNA-Seq ; Repetitive Sequences, Nucleic Acid/genetics ; Retroelements/genetics ; Signal Transduction/genetics
Chemical Substances	Heterochromatin ; Histones ; Retroelements ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; SETDB1 protein, mouse (EC 2.1.1.43) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2021-07-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-24532-8
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Article ; Online: m6A RNA methylation of major satellite repeat transcripts facilitates chromatin association and RNA:DNA hybrid formation in mouse heterochromatin.

Duda, Katarzyna J / Ching, Reagan W / Jerabek, Lisa / Shukeir, Nicholas / Erikson, Galina / Engist, Bettina / Onishi-Seebacher, Megumi / Perrera, Valentina / Richter, Florian / Mittler, Gerhard / Fritz, Katharina / Helm, Mark / Knuckles, Philip / Bühler, Marc / Jenuwein, Thomas

Nucleic acids research

2021 Volume 49, Issue 10, Page(s) 5568–5587

Abstract: Heterochromatin has essential functions in maintaining chromosome structure, in protecting genome integrity and in stabilizing gene expression programs. Heterochromatin is often nucleated by underlying DNA repeat sequences, such as major satellite ... ...

Abstract	Heterochromatin has essential functions in maintaining chromosome structure, in protecting genome integrity and in stabilizing gene expression programs. Heterochromatin is often nucleated by underlying DNA repeat sequences, such as major satellite repeats (MSR) and long interspersed nuclear elements (LINE). In order to establish heterochromatin, MSR and LINE elements need to be transcriptionally competent and generate non-coding repeat RNA that remain chromatin associated. We explored whether these heterochromatic RNA, similar to DNA and histones, may be methylated, particularly for 5-methylcytosine (5mC) or methyl-6-adenosine (m6A). Our analysis in mouse ES cells identifies only background level of 5mC but significant enrichment for m6A on heterochromatic RNA. Moreover, MSR transcripts are a novel target for m6A RNA modification, and their m6A RNA enrichment is decreased in ES cells that are mutant for Mettl3 or Mettl14, which encode components of a central RNA methyltransferase complex. Importantly, MSR transcripts that are partially deficient in m6A RNA methylation display impaired chromatin association and have a reduced potential to form RNA:DNA hybrids. We propose that m6A modification of MSR RNA will enhance the functions of MSR repeat transcripts to stabilize mouse heterochromatin.
MeSH term(s)	Adenosine/analogs & derivatives ; Adenosine/metabolism ; Animals ; DNA/metabolism ; Heterochromatin ; Methylation ; Mice ; Mouse Embryonic Stem Cells ; RNA/metabolism ; Tandem Repeat Sequences
Chemical Substances	Heterochromatin ; RNA (63231-63-0) ; DNA (9007-49-2) ; N-methyladenosine (CLE6G00625) ; Adenosine (K72T3FS567)
Language	English
Publishing date	2021-05-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkab364
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Article ; Online: Complete loss of H3K9 methylation dissolves mouse heterochromatin organization

Thomas Montavon / Nicholas Shukeir / Galina Erikson / Bettina Engist / Megumi Onishi-Seebacher / Devon Ryan / Yaarub Musa / Gerhard Mittler / Alexandra Graff Meyer / Christel Genoud / Thomas Jenuwein

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 16

Abstract: Histone H3K9 methylation (H3K9me) states define repressed chromatin in eukaryotic cells. Here the authors reveal complete loss of all H3K9me in mammalian cells through successive deletion of H3K9 methyltransferase genes that results in the dissolution of ...

Abstract	Histone H3K9 methylation (H3K9me) states define repressed chromatin in eukaryotic cells. Here the authors reveal complete loss of all H3K9me in mammalian cells through successive deletion of H3K9 methyltransferase genes that results in the dissolution of heterochromatin and the derepression of nearly all repeat families.
Keywords	Science ; Q
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: H1 linker histones silence repetitive elements by promoting both histone H3K9 methylation and chromatin compaction.

Healton, Sean E / Pinto, Hugo D / Mishra, Laxmi N / Hamilton, Gregory A / Wheat, Justin C / Swist-Rosowska, Kalina / Shukeir, Nicholas / Dou, Yali / Steidl, Ulrich / Jenuwein, Thomas / Gamble, Matthew J / Skoultchi, Arthur I

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 25, Page(s) 14251–14258

Abstract: Nearly 50% of mouse and human genomes are composed of repetitive sequences. Transcription of these sequences is tightly controlled during development to prevent genomic instability, inappropriate gene activation and other maladaptive processes. Here, we ... ...

Abstract	Nearly 50% of mouse and human genomes are composed of repetitive sequences. Transcription of these sequences is tightly controlled during development to prevent genomic instability, inappropriate gene activation and other maladaptive processes. Here, we demonstrate an integral role for H1 linker histones in silencing repetitive elements in mouse embryonic stem cells. Strong H1 depletion causes a profound de-repression of several classes of repetitive sequences, including major satellite, LINE-1, and ERV. Activation of repetitive sequence transcription is accompanied by decreased H3K9 trimethylation of repetitive sequence chromatin. H1 linker histones interact directly with Suv39h1, Suv39h2, and SETDB1, the histone methyltransferases responsible for H3K9 trimethylation of chromatin within these regions, and stimulate their activity toward chromatin in vitro. However, we also implicate chromatin compaction mediated by H1 as an additional, dominant repressive mechanism for silencing of repetitive major satellite sequences. Our findings elucidate two distinct, H1-mediated pathways for silencing heterochromatin.
MeSH term(s)	Animals ; Chromatin/metabolism ; Epigenomics ; Heterochromatin/metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/metabolism ; Methylation ; Methyltransferases/metabolism ; Mice ; Mouse Embryonic Stem Cells/metabolism ; Repetitive Sequences, Nucleic Acid/physiology ; Repressor Proteins/metabolism
Chemical Substances	Chromatin ; Heterochromatin ; Histones ; Repressor Proteins ; Suv39h1 protein, mouse (EC 2.1.1.) ; Methyltransferases (EC 2.1.1.-) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; SETDB1 protein, mouse (EC 2.1.1.43) ; Suv39h2 protein, mouse (EC 2.1.1.43)
Language	English
Publishing date	2020-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1920725117
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Article ; Online: Mammalian Su(var) genes in chromatin control.

Fodor, Barna D / Shukeir, Nicholas / Reuter, Gunter / Jenuwein, Thomas

Annual review of cell and developmental biology

2010 Volume 26, Page(s) 471–501

Abstract: Genetic screens in Drosophila have been instrumental in distinguishing approximately 390 loci involved in position effect variegation and heterochromatin stabilization. Most of the identified genes [so-called Su(var) and E(var) genes] are also conserved ... ...

Abstract	Genetic screens in Drosophila have been instrumental in distinguishing approximately 390 loci involved in position effect variegation and heterochromatin stabilization. Most of the identified genes [so-called Su(var) and E(var) genes] are also conserved in mammals, where more than 50 of their gene products are known to localize to constitutive heterochromatin. From these proteins, approximately 12 core heterochromatin components can be inferred. In addition, there are approximately 30 additional Su(var) and 10 E(var) factors that can, under distinct developmental options, interchange with constitutive heterochromatin and participate in the partitioning of the genome into repressed and active chromatin domains. A significant fraction of the Su(var) and E(var) factors are enzymes that respond to environmental and metabolic signals, thereby allowing both the variation and propagation of epigenetic states to a dynamic chromatin template. Moreover, the misregulation of human SU(VAR) and E(VAR) function can advance cancer and many other human diseases including more complex disorders. As such, mammalian Su(var) and E(var) genes and their products provide a rich source of novel targets for diagnosis of and pharmaceutical intervention in many human diseases.
MeSH term(s)	Animals ; Chromatin/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Heterochromatin ; Humans ; Methyltransferases/genetics ; Methyltransferases/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
Chemical Substances	Chromatin ; DNA-Binding Proteins ; Heterochromatin ; Repressor Proteins ; Methyltransferases (EC 2.1.1.-)
Language	English
Publishing date	2010
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1293750-2
ISSN	1530-8995 ; 1081-0706
ISSN (online)	1530-8995
ISSN	1081-0706
DOI	10.1146/annurev.cellbio.042308.113225
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Article ; Online: Pharmacological methyl group donors block skeletal metastasis in vitro and in vivo.

Shukeir, Nicholas / Stefanska, Barbara / Parashar, Surabhi / Chik, Flora / Arakelian, Ani / Szyf, Moshe / Rabbani, Shafaat A

British journal of pharmacology

2015 Volume 172, Issue 11, Page(s) 2769–2781

Abstract: Background and purpose: DNA hypomethylation was previously implicated in metastasis. In the present study, we examined whether methyl supplementation with the universal methyl donor S-adenosylmethionine (SAM) inhibits prostate cancer associated skeletal ...

Abstract	Background and purpose: DNA hypomethylation was previously implicated in metastasis. In the present study, we examined whether methyl supplementation with the universal methyl donor S-adenosylmethionine (SAM) inhibits prostate cancer associated skeletal metastasis. Experimental approach: Highly invasive human prostate cancer cells PC-3 and DU-145 were treated with vehicle alone, S-adenosylhomocysteine (SAH) or SAM and their effects on tumour cell proliferation, invasion, migration and colony formation were monitored. For in vivo studies, control (SAH) and SAM-treated PC-3 cells were injected into the tibia of Fox chase SCID mice and skeletal lesions were determined by X-ray and μCT. To understand possible mechanisms involved, we delineated the effect of SAM on the genome-wide methylation profile of PC-3 cells. Key results: Treatment with SAM resulted in a dose-dependent inhibition of tumour cell proliferation, invasion, cell migration, colony formation and cell cycle characteristics. Animals injected with 250 μM SAM-treated cells developed significantly smaller skeletal lesions, which were associated with increases in bone volume to tumour volume ratio and connectivity density as well as decreased trabecular spacing. Genome-wide methylation analysis showed differential methylation in several key signalling pathways implicated in prostate cancer including the signal transducer and activator of transcription 3 (STAT3) pathway. A selective STAT3 inhibitor decreased tumour cell invasion, effects which were less pronounced as compared with SAM. Conclusions and implications: These studies provide a possible mechanism for the role of DNA demethylation in the development of skeletal metastasis and a rationale for the use of hypermethylation pharmacological agents to impede the development and progression of skeletal metastasis.
MeSH term(s)	Adenocarcinoma/genetics ; Adenocarcinoma/secondary ; Animals ; Bone Neoplasms/genetics ; Bone Neoplasms/secondary ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Movement/genetics ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; DNA Methylation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; In Vitro Techniques ; Male ; Mice ; Mice, SCID ; Neoplasm Invasiveness/genetics ; Neoplasm Metastasis/genetics ; Neoplasm Transplantation ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; S-Adenosylmethionine/pharmacology ; Tibia/diagnostic imaging ; Tibia/drug effects ; X-Ray Microtomography
Chemical Substances	S-Adenosylmethionine (7LP2MPO46S)
Language	English
Publishing date	2015-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.13102
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Article ; Online: Major satellite repeat RNA stabilize heterochromatin retention of Suv39h enzymes by RNA-nucleosome association and RNA:DNA hybrid formation.

Velazquez Camacho, Oscar / Galan, Carmen / Swist-Rosowska, Kalina / Ching, Reagan / Gamalinda, Michael / Karabiber, Fethullah / De La Rosa-Velazquez, Inti / Engist, Bettina / Koschorz, Birgit / Shukeir, Nicholas / Onishi-Seebacher, Megumi / van de Nobelen, Suzanne / Jenuwein, Thomas

eLife

2017 Volume 6

Abstract: The Suv39h1 and Suv39h2 histone lysine methyltransferases are hallmark enzymes at mammalian heterochromatin. We show here that the mouse Suv39h2 enzyme differs from Suv39h1 by containing an N-terminal basic domain that facilitates retention at mitotic ... ...

Abstract	The Suv39h1 and Suv39h2 histone lysine methyltransferases are hallmark enzymes at mammalian heterochromatin. We show here that the mouse Suv39h2 enzyme differs from Suv39h1 by containing an N-terminal basic domain that facilitates retention at mitotic chromatin and provides an additional affinity for major satellite repeat RNA. To analyze an RNA-dependent interaction with chromatin, we purified native nucleosomes from mouse ES cells and detect that Suv39h1 and Suv39h2 exclusively associate with poly-nucleosomes. This association was attenuated upon RNaseH incubation and entirely lost upon RNaseA digestion of native chromatin. Major satellite repeat transcripts remain chromatin-associated and have a secondary structure that favors RNA:DNA hybrid formation. Together, these data reveal an RNA-mediated mechanism for the stable chromatin interaction of the Suv39h KMT and suggest a function for major satellite non-coding RNA in the organization of an RNA-nucleosome scaffold as the underlying structure of mouse heterochromatin.
MeSH term(s)	Animals ; DNA/metabolism ; Heterochromatin/metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Methyltransferases/metabolism ; Mice ; Nucleic Acid Hybridization ; Nucleosomes/metabolism ; RNA/metabolism ; Repetitive Sequences, Nucleic Acid ; Repressor Proteins/metabolism
Chemical Substances	Heterochromatin ; Nucleosomes ; Repressor Proteins ; RNA (63231-63-0) ; DNA (9007-49-2) ; Suv39h1 protein, mouse (EC 2.1.1.) ; Methyltransferases (EC 2.1.1.-) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Suv39h2 protein, mouse (EC 2.1.1.43)
Language	English
Publishing date	2017-08-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.25293
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Article ; Online: Major satellite repeat RNA stabilize heterochromatin retention of Suv39h enzymes by RNA-nucleosome association and RNA:DNA hybrid formation

Oscar Velazquez Camacho / Carmen Galan / Kalina Swist-Rosowska / Reagan Ching / Michael Gamalinda / Fethullah Karabiber / Inti De La Rosa-Velazquez / Bettina Engist / Birgit Koschorz / Nicholas Shukeir / Megumi Onishi-Seebacher / Suzanne van de Nobelen / Thomas Jenuwein

eLife, Vol

2017 Volume 6

Abstract	The Suv39h1 and Suv39h2 histone lysine methyltransferases are hallmark enzymes at mammalian heterochromatin. We show here that the mouse Suv39h2 enzyme differs from Suv39h1 by containing an N-terminal basic domain that facilitates retention at mitotic chromatin and provides an additional affinity for major satellite repeat RNA. To analyze an RNA-dependent interaction with chromatin, we purified native nucleosomes from mouse ES cells and detect that Suv39h1 and Suv39h2 exclusively associate with poly-nucleosomes. This association was attenuated upon RNaseH incubation and entirely lost upon RNaseA digestion of native chromatin. Major satellite repeat transcripts remain chromatin-associated and have a secondary structure that favors RNA:DNA hybrid formation. Together, these data reveal an RNA-mediated mechanism for the stable chromatin interaction of the Suv39h KMT and suggest a function for major satellite non-coding RNA in the organization of an RNA-nucleosome scaffold as the underlying structure of mouse heterochromatin.
Keywords	Suv39h1 ; Suv39h2 ; major satellite repeat ; pericentric heterochromatin ; non-coding RNA ; RNA:DNA hybrids ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2017-08-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
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Article: Alteration of the methylation status of tumor-promoting genes decreases prostate cancer cell invasiveness and tumorigenesis in vitro and in vivo.

Shukeir, Nicholas / Pakneshan, Pouya / Chen, Gaoping / Szyf, Moshe / Rabbani, Shafaat A

Cancer research

2006 Volume 66, Issue 18, Page(s) 9202–9210

Abstract: We tested the hypothesis that cell invasiveness and tumorigenesis are driven by hypomethylation of genes involved in tumor progression. Highly invasive human prostate cancer cells PC-3 were treated with either the methyl donor S-adenosylmethionine (SAM) ... ...

Abstract	We tested the hypothesis that cell invasiveness and tumorigenesis are driven by hypomethylation of genes involved in tumor progression. Highly invasive human prostate cancer cells PC-3 were treated with either the methyl donor S-adenosylmethionine (SAM) or methyl DNA-binding domain protein 2 antisense oligonucleotide (MBD2-AS). Both treatments resulted in a dose- and time-dependent inhibition of key genes, such as urokinase-type plasminogen activator (uPA), matrix metalloproteinase-2 (MMP-2), and vascular endothelial growth factor expression to decrease tumor cell invasion in vitro. No change in the levels of expression of genes already known to be methylated in late-stage prostate cancer cells, such as glutathione S-transferase P1 and androgen receptor, was seen. Inoculation of PC-3 cells pretreated with SAM and MBD2-AS into the flank of male BALB/c nu/nu mice resulted in the development of tumors of significantly smaller volume compared with animals inoculated with PC-3 cells treated with vehicle alone or MBD2 scrambled oligonucleotide. Immunohistochemical analysis of tumors showed the ability of SAM and MBD2-AS to significantly decrease tumoral uPA and MMP-2 expression along with levels of angiogenesis and survival pathway signaling molecules. Bisulfite sequencing analysis of tumoral genomic DNA showed that inhibition of both uPA and MMP-2 expression was due to methylation of their 5' regulatory region. These studies support the hypothesis that DNA hypomethylation controls the activation of multiple tumor-promoting genes and provide valuable insight into developing novel therapeutic strategies against this common disease, which target the demethylation machinery.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/pathology ; DNA Methylation ; DNA-Binding Proteins/biosynthesis ; DNA-Binding Proteins/deficiency ; DNA-Binding Proteins/genetics ; Down-Regulation ; Genetic Therapy/methods ; Humans ; Male ; Matrix Metalloproteinase 2/biosynthesis ; Matrix Metalloproteinase 2/genetics ; Mice ; Mice, Inbred BALB C ; Neoplasm Invasiveness ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/therapy ; Oligonucleotides, Antisense/genetics ; Plasminogen Activators/biosynthesis ; Plasminogen Activators/deficiency ; Plasminogen Activators/genetics ; Prostatic Neoplasms/blood supply ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/therapy ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; S-Adenosylmethionine/pharmacology ; Transfection ; Vascular Endothelial Growth Factor A/biosynthesis ; Vascular Endothelial Growth Factor A/deficiency ; Vascular Endothelial Growth Factor A/genetics ; Xenograft Model Antitumor Assays
Chemical Substances	DNA-Binding Proteins ; MBD2 protein, human ; Oligonucleotides, Antisense ; RNA, Messenger ; Vascular Endothelial Growth Factor A ; S-Adenosylmethionine (7LP2MPO46S) ; Plasminogen Activators (EC 3.4.21.-) ; Matrix Metalloproteinase 2 (EC 3.4.24.24)
Language	English
Publishing date	2006-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-06-1954
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Article: Prostate secretory protein of 94 amino acids (PSP-94) and its peptide (PCK3145) as potential therapeutic modalities for prostate cancer.

Shukeir, Nicholas / Garde, Seema / Wu, Jinzi J / Panchal, Chandra / Rabbani, Shafaat A

Anti-cancer drugs

2005 Volume 16, Issue 10, Page(s) 1045–1051

Abstract: This review focuses on the promising roles of prostate secretory protein of 94 amino acids (PSP-94) and one of its derived peptides (PCK3145) as potential therapeutic modalities for prostate cancer and its associated complications. Evaluation of these ... ...

Abstract	This review focuses on the promising roles of prostate secretory protein of 94 amino acids (PSP-94) and one of its derived peptides (PCK3145) as potential therapeutic modalities for prostate cancer and its associated complications. Evaluation of these compounds was carried out in vitro and in vivo using syngeneic models of rat prostate cancer. Overproduction of parathyroid hormone-related protein (PTHrP) results in the development of hypercalcemia of malignancy in several malignancies including prostate cancer. In order to evaluate the effect of PSP-94 and PCK3145 on prostate cancer progression, the rat Dunning R3227 MatLyLu cell line transfected with full-length cDNA encoding PTHrP (MatLyLu-PTHrP) was used. As the main pathogenetic factor of hypercalcemia of malignancy, overexpression of PTHrP was aimed at mimicking the hypercalcemic nature seen in patients suffering from late-stage cancer. In vitro studies showed that PSP-94 and PCK3145 can cause a dose-dependent inhibition in the growth of MatLyLu-PTHrP cells. For in vivo studies, male Copenhagen rats were inoculated either s.c. into the right flank or directly into the left ventricle via intracardiac (i.c.) inoculation with MatLyLu-PTHrP cells. In these models, s.c. injection of MatLyLu cells results in the development of primary tumor growth, whereas i.c. inoculation routinely results in the development of experimental skeletal metastases in the lumbar vertebrae causing hind-limb paralysis. Administration of PSP-94 and PCK3145 into tumor-bearing animals resulted in a dose-dependent inhibition of primary tumor growth, and tumoral and plasma PTHrP levels, and in the reduction of plasma calcium levels. Additionally, treatment with PSP-94 or PCK3145 caused an inhibition of skeletal metastases resulting in a significant delay in the development of hind-limb paralysis. Interestingly, equimolar concentrations of PCK3145 were shown to be more effective in delaying the development of experimental skeletal metastases as compared to PSP-94. One of the possible mechanisms of action of these modalities is through the induction of apoptosis which was observed by both in-vitro and in-vivo analyses of MatLyLu-PTHrP cells and tumors. Several intracellular mechanisms can also be involved in inhibiting PTHrP production and anti-tumor effects of PSP-94 and PCK3145. Collectively, these studies warrant the continued clinical development of these agents as therapeutic agents for patients with hormone-refractory prostate cancer.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Bone Neoplasms/prevention & control ; Bone Neoplasms/secondary ; Calcium/blood ; Cell Line, Tumor ; Humans ; Male ; Parathyroid Hormone-Related Protein/blood ; Peptide Fragments/therapeutic use ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/pathology ; Prostatic Secretory Proteins/therapeutic use ; Rats
Chemical Substances	Antineoplastic Agents ; Parathyroid Hormone-Related Protein ; Peptide Fragments ; Prostatic Secretory Proteins ; beta-microseminoprotein ; tigapotide (1WZ6S45S94) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2005-09-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1065301-6
ISSN	1473-5741 ; 0959-4973
ISSN (online)	1473-5741
ISSN	0959-4973
DOI	10.1097/00001813-200511000-00002
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