The role of the histone H3 variant CENPA in prostate cancer

Abstract

Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized. The centromeric histone H3 variant centromere protein A (CENPA) is an epigenetic mark that determines centromere identity. Here, using an array of approaches, including RNA-sequencing and ChIP-sequencing analyses, immunohistochemistry-based tissue microarrays, and various cell biology assays, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines and that the level of CENPA expression correlates with the disease stage in a large cohort of patients. Gain-of-function and loss-of-function experiments confirmed that CENPA promotes prostate cancer cell line growth. The results from the integrated sequencing experiments suggested a previously unidentified function of CENPA as a transcriptional regulator that modulates expression of critical proliferation, cell-cycle, and centromere/kinetochore genes. Taken together, our findings show that CENPA overexpression is crucial to prostate cancer growth. Overexpression of centromeric proteins has been identified in a number of human malignancies, but the functional and mechanistic contributions of these proteins to disease progression have not been characterized. The centromeric histone H3 variant centromere protein A (CENPA) is an epigenetic mark that determines centromere identity. Here, using an array of approaches, including RNA-sequencing and ChIP-sequencing analyses, immunohistochemistry-based tissue microarrays, and various cell biology assays, we demonstrate that CENPA is highly overexpressed in prostate cancer in both tissue and cell lines and that the level of CENPA expression correlates with the disease stage in a large cohort of patients. Gain-of-function and loss-of-function experiments confirmed that CENPA promotes prostate cancer cell line growth. The results from the integrated sequencing experiments suggested a previously unidentified function of CENPA as a transcriptional regulator that modulates expression of critical proliferation, cell-cycle, and centromere/kinetochore genes. Taken together, our findings show that CENPA overexpression is crucial to prostate cancer growth. Centromeres are cellular structures that are necessary for the propagation of hereditary information (1Cleveland D.W. Mao Y. Sullivan K.F. Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling.Cell. 2003; 112 (12600307): 407-42110.1016/S0092-8674(03)00115-6Abstract Full Text Full Text PDF PubMed Scopus (822) Google Scholar, 2Hayden K.E. Human centromere genomics: now it's personal.Chromosome Res. 2012; 20 (22801774): 621-63310.1007/s10577-012-9295-yCrossref PubMed Scopus (25) Google Scholar). Located centric to the ends of each chromosome, centromeres provide the structural foundation for kinetochores, multimeric complexes that serve as molecular interfaces between microtubule spindle fibers and individual chromatids during mitosis (1Cleveland D.W. Mao Y. Sullivan K.F. Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling.Cell. 2003; 112 (12600307): 407-42110.1016/S0092-8674(03)00115-6Abstract Full Text Full Text PDF PubMed Scopus (822) Google Scholar). The centromere–kinetochore–microtubule interaction facilitates separation of the sister chromatids as mitosis proceeds from metaphase to anaphase. Centromeres are thus essential to ensuring faithful segregation of chromosomes in actively dividing cells. Efforts to study human centromeres have focused on the epigenetics that drive centromere assembly (3Hayashi T. Fujita Y. Iwasaki O. Adachi Y. Takahashi K. Yanagida M. Mis16 and Mis18 are required for CENP-A loading and histone deacetylation at centromeres.Cell. 2004; 118 (15369671): 715-72910.1016/j.cell.2004.09.002Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 4Kim I.S. Lee M. Park K.C. Jeon Y. Park J.H. Hwang E.J. Jeon T.I. Ko S. Lee H. Baek S.H. Kim K.I. Roles of Mis18α in epigenetic regulation of centromeric chromatin and CENP-A loading.Mol. Cell. 2012; 46 (22516971): 260-27310.1016/j.molcel.2012.03.021Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). α-Satellite sequences that define centromere DNA are primarily occupied by a centromere-specific histone H3 variant known as CENPA (3Hayashi T. Fujita Y. Iwasaki O. Adachi Y. Takahashi K. Yanagida M. Mis16 and Mis18 are required for CENP-A loading and histone deacetylation at centromeres.Cell. 2004; 118 (15369671): 715-72910.1016/j.cell.2004.09.002Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar, 5Foltz D.R. Jansen L.E. Black B.E. Bailey A.O. Yates 3rd, J.R. Cleveland D.W. The human CENP-A centromeric nucleosome-associated complex.Nat. Cell Biol. 2006; 8 (16622419): 458-46910.1038/ncb1397Crossref PubMed Scopus (520) Google Scholar). CENPA is a functionally conserved ∼17-kDa molecule that forms a centromere-specific nucleosome with H2A, H2B, and H4 (6Hasson D. Panchenko T. Salimian K.J. Salman M.U. Sekulic N. Alonso A. Warburton P.E. Black B.E. The octamer is the major form of CENP-A nucleosomes at human centromeres.Nat. Struct. Mol. Biol. 2013; 20 (23644596): 687-69510.1038/nsmb.2562Crossref PubMed Scopus (141) Google Scholar). Proper CENPA localization is an ubiquitin E3 ligase–dependent process requiring ubiquitination of lysine 124 for engagement with the CENPA-specific chaperone HJURP (7Niikura Y. Kitagawa R. Ogi H. Abdulle R. Pagala V. Kitagawa K. CENP-A K124 ubiquitylation is required for CENP-A deposition at the centromere.Dev. Cell. 2015; 32 (25727006): 589-60310.1016/j.devcel.2015.01.024Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). HJURP subsequently facilitates the incorporation of newly synthesized CENPA into nucleosomes occupying replicated α-satellite DNA (8Barnhart M.C. Kuich P.H. Stellfox M.E. Ward J.A. Bassett E.A. Black B.E. Foltz D.R. HJURP is a CENP-A chromatin assembly factor sufficient to form a functional de novo kinetochore.J. 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The CENP-L-N complex forms a critical node in an integrated meshwork of interactions at the centromere–kinetochore interface.Mol. Cell. 2015; 60 (26698661): 886-89810.1016/j.molcel.2015.10.027Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). The CCAN serves as a multimeric interface between the DNA-enveloped CENPA nucleosomes and the KNL-1–Mis12–Ndc80 complex network that comprises the outer kinetochore and directly interacts with the microtubule spindle fibers (12Schleiffer A. Maier M. Litos G. Lampert F. Hornung P. Mechtler K. Westermann S. CENP-T proteins are conserved centromere receptors of the Ndc80 complex.Nat. Cell Biol. 2012; 14 (22561346): 604-61310.1038/ncb2493Crossref PubMed Scopus (129) Google Scholar). CENPA and its associated proteins therefore represent structural components that are essential to the integrity of cell division, and appropriate genomic localization of centromeric proteins is consequently a critical event in the cell cycle. Diseases of uncontrolled cell division, particularly cancer, are thus compelling to examine from the epigenetic perspective of centromere biology, primarily as it pertains to the key epigenetic mark CENPA. A number of studies have identified aberrant expression of centromeric/kinetochore proteins in cancers, where overexpression is predictive of survival and response to therapy, although their mechanistic contribution to cancer pathogenesis remains elusive (13Thiru P. Kern D.M. McKinley K.L. Monda J.K. Rago F. Su K.-C. Tsinman T. Yarar D. Bell G.W. Cheeseman I.M. Kinetochore genes are coordinately up-regulated in human tumors as part of a FoxM1-related cell division program.Mol. Biol. Cell. 2014; 25 (24829384): 1983-199410.1091/mbc.e14-03-0837Crossref PubMed Google Scholar, 14Tomonaga T. Matsushita K. Ishibashi M. Nezu M. Shimada H. Ochiai T. Yoda K. Nomura F. 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D.R. of in the human 2015; PubMed Scopus Google Scholar). that CENPA is overexpressed in tissue to and with the contributions of centromeric components CENPA to cell division, suggested a focused of these components in that in the of cancer is where a is predictive of G. S. H. P. J. D.M. of for prostate cancer in a J. Cancer. 2013; PubMed Scopus Google Scholar, R. K. M.E. 3rd, M. A. predicts and survival in prostate cancer with an of in Res. 2004; 10 PubMed Scopus Google Scholar). are for prostate cancer, remains the in and the of in Scholar). and are disease and as and are a at prostate cancer 2014; PubMed Scopus Google Scholar). of the we set in the prostate tissue cohort from tissue R. A. Y. J.R. J.R. S. A. X. D.R. of in the human 2015; PubMed Scopus Google Scholar). expression of centromeric components in prostate cancer tissue to their and on a that of these components as part of the that is associated with disease W. Mao J.-H. Zhu W. Jain A.K. Liu K. Brown J.B. Karpen G.H. Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy.Nat. Commun. 2016; 7 (27577169): 1261910.1038/ncomms12619Crossref PubMed Scopus (122) Google Scholar). CENPA from of genes for its in centromere biology, for and highly conserved and a in expression with disease progression J.A. J.A. for the Res. 46 PubMed Scopus Google Scholar). in at the protein level through prostate tissue for overexpression of CENPA that with disease of the prostate tissue an the of a between elevated CENPA expression and prostate cancer of CENPA expression in cancer cell line to for focused molecular overexpression of CENPA in prostate cancer cell as with lines The cell line a of its to cell lines we Taken together, CENPA is a functionally factor in prostate cancer as in a large number of and in prostate cancer cell and an in its expression at the and protein is highly with The of CENPA in prostate cancer the of overexpression a functional in disease pathogenesis and thus a of CENPA expression to the in prostate cancer to with that functional to in human cancer and tissue facilitates genes of in a a large of thus CENPA to the expression of protein to its contribution to prostate cancer CENPA expression with a number of previously identified prostate cancer pathogenesis including and and and marker in our a for CENPA in cellular CENPA not with cancer A and and a process that is of a molecular that is in prostate cancer with cellular genes and pathogenesis of CENPA as a to a process that is in prostate cancer we that CENPA expression in cell the for and to on the genes from our CENPA expression in prostate cancer D.W. and of large gene using 2009; PubMed Scopus Google Scholar). a between CENPA gene expression and that kinetochores, and cell division and that genes components of the CCAN by our and genes known to in cellular proliferation, cell and centromere/kinetochore in these gene set confirmed in gene for cell cell division, and mitosis and Taken together, CENPA expression is to gene that that proliferation, cell and centromere/kinetochore integrity in prostate between CENPA and is the CENPA in the structural integrity of the is CENPA function in human therefore and experiments in cell lines CENPA CENPA. at sufficient to of CENPA and A and CENPA to a on and prostate cancer and and CENPA in prostate cancer results in an of in that to to through the cell and and overexpression of CENPA in the prostate cell line to a and of CENPA not demonstrate with that with of CENPA B.E. Jansen L.E. Foltz D.R. Cleveland D.W. Centromere by nucleosomes with histone H3 the CENP-A Cell. 25 Full Text Full Text PDF PubMed Scopus Google Scholar). Taken together, our show that CENPA is an essential factor for progression through the cell and that overexpression of prostate cancer cells. of deposition in the of CENPA overexpression and the overexpression of CENPA in prostate cancer, we by sequencing to and binding for CENPA in prostate to the using a we previously that α-satellite DNA from the of the CENPA R. S. A.K. P.W. M. Wang M. F. A. D.M. molecular to study human centromere Res. PubMed Scopus Google Scholar). identified binding in the prostate cancer cell line and and of a is in the of a cell that is critical for progression through that identified in our gene expression the of CENPA by with previously that CENPA its Baek S. S. M. J. T. Y. 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CENPA is a centromere-specific histone H3 variant overexpressed in cancer functional contributions to have CENPA to of the centromere genes in and the that CENPA a in gene thus on cell lines to CENPA the gene expression of genes by CENPA. at sufficient to and of CENPA to the in the cell line by genes that between each A and The genes transcriptional in the of CENPA and on the we identified between by CENPA and that are and between the and from prostate cancer cell lines for identified a number of genes essential to cellular and centromere/kinetochore integrity that both by CENPA and in the of CENPA and and genes expression to CENPA expression in prostate cancer with CENPA as as by CENPA. cell division to an our with findings in findings that CENPA a regulator of for genes for and cell progression in prostate cancer although the cell as as functional required to of centromeric molecular in number in the form of α-satellite are cancer in both cell lines and tissue A.K. M. I. R. D.M. R. The of Centromeres in Scholar). the H3 variant that α-satellite gene as transcriptional of genes for cell as overexpressed in studies are necessary to functionally the localization to the α-satellite The centromeric histone H3 variant CENPA is overexpressed in cancer and has the to to genomic that of the centromere in the of the functional of the localization of CENPA in the of has been for the that CENPA have functional through an as a regulator of gene expression in prostate CENPA is and in prostate cancer D. N. G. H. W. J. X. of prostate 2015; Full Text Full Text PDF PubMed Scopus Google Scholar, G. J.A. J. J. P. M. A. T. prostate cancer by Full Text Full Text PDF PubMed Scopus Google Scholar). the genomic of the CENPA the that are the of CENPA expression are to histone aberrant in have been has been that to cell division and is a function of its as a structural node for the CCAN and KNL-1–Mis12–Ndc80 complex its in the centromere is we now that deposition of CENPA in prostate cancer an in cell division by critical proliferation, cell and centromere/kinetochore genes. thus an critical in protein cellular overexpressed in the of experiments necessary to is using we to and from the prostate cancer cell the of CENPA overexpression in cancer, it is that CENPA through transcriptional regulation is a cancer that although centromeric/kinetochore proteins are in cancer, overexpression of centromeric/kinetochore is a identified in (13Thiru P. Kern D.M. McKinley K.L. Monda J.K. Rago F. Su K.-C. Tsinman T. Yarar D. Bell G.W. Cheeseman I.M. Kinetochore genes are coordinately up-regulated in human tumors as part of a FoxM1-related cell division program.Mol. Biol. Cell. 2014; 25 (24829384): 1983-199410.1091/mbc.e14-03-0837Crossref PubMed Google Scholar). findings a epigenetic by of CENPA drive gene expression of critical proliferation, cell and centromere/kinetochore that previously identified through cancer D.R. P. E. J. X. E. V. S. A. J. R. F. of PubMed Scopus Google Scholar). the and molecular in prostate cancer, not by a a that we confirmed in tissue expression in response to CENPA as an epigenetic factor that to progression S. H. expression and a of progression of prostate PubMed Scopus Google Scholar). we that expression with CENPA expression in prostate cancer tissue we show that prostate cancer tissue and cell lines that of of the α-satellite centromere is sufficient for functional centromeres M. Salimian K.J. Panchenko T. Cleveland D.W. Black B.E. Jansen L.E. The of centromeric 2014; PubMed Scopus Google Scholar). of CENPA and CENPA binding to α-satellite in prostate cancer cell lines in a cell overexpression of CENPA in cells. findings are with the that CENPA cellular in the of overexpression and our show that the chaperone that directs CENPA to centromeric with CENPA expression in prostate cancer in that overexpressed CENPA is to gene through interaction with a protein that has been previously been to overexpressed in prostate cancer J. T. promotes prostate cancer of Biol. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). is thus that HJURP a chaperone function for CENPA in prostate cancer, although CENPA and HJURP CENPA and necessary to the of a that studies that have transcriptional in the of CENPA have in gene expression Y. Zhu S. D. H. Liu L. X. Wang L. H. Zhu M. centromere protein A 2011; PubMed Scopus Google Scholar, N. A. H. T. S. H. A. G. of the centromeric histone variant in human on the chaperone Cell. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, V. P. T. T. E. D. W. Brown W. CENP-A is required for segregation and kinetochore of Cell Biol. 2005; 25 PubMed Scopus Google Scholar). CENPA overexpression is cancer it that gene expression in prostate cancer with CENPA is of CENPA for not cancer cell lines tissue to contributions to our primary cancer cell lines the of our to that in the of cell line to the findings in of genomic to of the gene expression to CENPA that we a of mitotic that cell thus cell division and the transcriptional cell in cell lines of CENPA. the of mitotic in the of CENPA gene expression to CENPA are in part to the cellular response to genomic our findings that demonstrate CENPA at the it is that the transcriptional to genomic is to the transcriptional by CENPA we show that the centromeric histone H3 variant CENPA is overexpressed in a of with prostate cancer, and overexpression correlates with disease CENPA is to the of prostate cancer and has a previously function as an epigenetic regulator of transcriptional activity genes for proliferation, cell and centromere and kinetochore integrity in prostate CENPA by thus uncontrolled in prostate and The of CENPA overexpression in malignancies, in to prostate cancer, that CENPA and in its for and prostate cancer cell lines in with and as the cell and prostate cancer cell lines in with and The and cell lines in with and cell lines at in a cell by for at the of and for on a of primary cancer and cancer cell lines from The the for and as previously to CENPA expression in a cancer R. A. Y. J.R. J.R. S. A. X. D.R. of in the human 2015; PubMed Scopus Google Scholar). to the prostate tissue cohort to CENPA expression at of CENPA the cancer cohort to studies genes. genes the in a for of genes by the and to The as as CENPA expression in by on a tissue using a prostate prostate cancer and prostate cancer in on the by the of at in to the of that A subsequently of with the for each The on The to from cell to genomic by the and to 25 The for and for and subsequently synthesized by A to and subsequently as an an of the for are in in each and of the from The in for and in for an at and to The subsequently on and to at for The in for at with in at the with The using to CENPA and as primary of CENPA using the of and a and for DNA subsequently using a and to the of for and with in the of 8 the in the of through with at a of response by and CENPA overexpression using the by an and as for the with in the of 8 the in and to to by the of Overexpression by and of are in the the of the in and with with 10 and and as using The in at The by to by by where the are from from using the for and The in in at The to and subsequently to at to of the 7 The with and subsequently with The with for 10 with and The to of at and subsequently by The at in and in in The for to by of Cell using as previously J. Liu S. M. M.M. M.C. for of cell Commun. 2015; PubMed Scopus Google using a CENPA DNA and DNA for sequencing using the to the in with the of with the with to to the of each by to and The to using with to the of between to CENPA The for using the and The with using Lee S. M.A. gene set for Res. 2014; PubMed Scopus Google Scholar). as and integrity using an using the to the in with the of with the with to and results through a to and to a from gene expression and genes using S. M.A. a functional for with 2016; 32 PubMed Scopus Google Scholar). RNA-sequencing and ChIP-sequencing are in the with and are the are to and for and and for with centromere protein constitutive centromere-associated network set for and gene set sequencing sequencing gene

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