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[Cancer Research 62, 647-651, February 1, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

High Mobility Group Protein I(Y)

A Candidate Architectural Protein for Chromosomal Rearrangements in Prostate Cancer Cells1

Natsuki Takaha, Anita L. Hawkins, Constance A. Griffin, William B. Isaacs and Donald S. Coffey2

Departments of Urology [N. T., W. B. I., D. S. C.] and Pathology [A. L. H., C. A. G.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
The extent of chromosomal rearrangements correlates positively with the level of expression of the nuclear matrix high mobility group (HMG) proteins HMGI(Y) when tested in three human prostate cancer cell lines (PC-3 > DU-145 > LNCaP). HMGI(Y), topoisomerase II, and A-T-rich sequences have been reported to be located at the base of the DNA loop domains in both the nucleus and chromosome and are juxtapositioned for chromosomal rearrangement. Transfecting and expressing full-length HMG-I into the LNCaP cell markedly enhanced the presence and heterogeneity of unbalanced (nonreciprocal) chromosomal rearrangements but not of balanced rearrangements. Unbalanced chromosomal rearrangements are common in solid human tumors.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Abnormalities in nuclear shape and chromosome structure have been hallmarks of the cancer cell since first described by Rudolph Virchow in 1863 and Theodore Boveri in 1902 (1) . These structural and genetic instabilities are now believed to be the driving force in developing tumor cell heterogeneity that provides the tumor a variety of subclones for selection for resistance to all forms of therapy (2 , 3) . Although there are many specific types of genetic changes associated with cancer, chromosome instability is a common genetic feature of solid tumors (3, 4, 5) . Chromosome abnormalities can be classified into three types: ploidy instability, variations in copy number of individual chromosomes, and chromosomal structural instability. The latter includes chromosomal rearrangements that are common solid tumor markers. Structural changes may simply rearrange genetic material, such as inversions or balanced translocations, or alternatively may result in a net gain or loss of genetic material, as in duplications, deletions, or unbalanced translocations. Balanced translocations [e.g., t(9;22) and t(8;14)] are more commonly observed in leukemias and lymphomas, whereas multiple unbalanced translocations are more commonly observed in solid tumors. Changes in chromosomal structure have been related to defects in DNA repair of double strand breaks, abnormalities in mitotic checkpoints, and abnormalities in nuclear structural proteins that may be related to chromosome structure (3 , 4) . The nucleus is a dynamic structure, and the nuclear matrix is a residual scaffold structure that is observed after extraction of the histones, soluble proteins, and lipids. The nuclear matrix helps to define the overall shape of the nucleus and contributes to the three-dimensional higher order organization of DNA in the interphase nucleus. The nuclear matrix elements also appear in the residual chromosomal scaffold structure (3 , 6 , 7) . The nucleus and chromosome are characterized by DNA loop domains of 50–100 kbp size attached to a matrix or scaffold. The nucleus contains ~50,000 of these DNA loops with special sequences termed MARS3 (also termed scaffold attachment regions) located at the base of the loop at the site of attachment to the nuclear matrix proteins (8) . The MARS contain A-T-rich sequences and are associated with binding sites for topoisomerase II and HMGI(Y), each of which are major components of both the nuclear matrix and the chromosome scaffold (9, 10, 11) . The composition of the nuclear matrix proteins has been found to change in relation to the biological function of the cell and with transformation to cancer (12) . The matrix also has been reported to contain the fixed sites for DNA replication with adjacent DNA loops representing replicons being reeled down through the replicating centers (13) . These replication sites are attached to the nuclear matrix and are in close proximity to topoisomerase II (14) and HMGI(Y), which are also at the base of the loops (7, 8, 9, 10, 11) . As will be discussed, the common location of these components are juxtapositioned to be involved in DNA rearrangement.

Here we investigate the role of HMGI(Y), one of the HMG nuclear matrix proteins and a component of both the interphase nucleus and the residual scaffold of the chromosome (9) . We believe HMGI(Y) is a candidate protein for involvement in chromosomal rearrangements in cancer, based on the following three biological features of HMGI(Y):

(a) HMGI(Y) binds to a specific structure or sequence of DNA in the minor groove of DNA, such as A-T-rich sequences (9 , 15) . HMGI(Y) also binds to DNA four-way junctions in vitro that mimic the Holiday junctions that are formed as an intermediate DNA cross-over structure during homologous recombination (16 , 17) . HMGI(Y) also binds to DNA base unpairing regions, which are located in the core sequences of the MARS. The MARS are located at the base of DNA loop domains and are also associated with the scaffolding of the chromosome that is enriched with A-T sequences (18) .

(b) HMGI(Y) induces changes in DNA architecture. HMGI(Y) induces both positive and negative supercoils into plasmid DNA and also binds and bends DNA by binding to the A-T-rich sequences in the minor groove of DNA (19) .

(c) HMGI(Y) enhances the integration of HIV cDNA into the host DNA in vitro. All of the above features of HMGI(Y) in altering DNA architecture could play a role in directing and enhancing nonhomologous DNA rearrangements, which produce the multiple unbalanced translocation observed in solid tumors.

In this study, we investigated the level of HMGI (Y) expression in three human prostate cancer cell lines (LNCaP, DU145, and PC-3). These cell lines have been reported to exhibit marked differences in their degree of DNA rearrangement and chromosomal abnormalities as assessed by G-banding and the SKY techniques (20 , 21) . We have transfected and overexpressed HMGI(Y) in LNCaP, a line with only balanced rearrangements and a very stable karyotype over time, to test whether this would result in an increase in new unbalanced chromosomal translocations of the type observed more commonly in solid tumors.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cell Culture and Transfection.
LNCaP, DU145, and PC-3 human prostate cancer cell lines were obtained from America Type Culture Collection (Rockville MD) and were grown in the recommended medium with minor modification. All of the cell lines were grown in a humidified incubator at 37°C under 5% CO2. LNCaP cells were transfected with plasmids expressing mouse HMG-I [longer isoform of HMGI(Y) encoding 107 amino acids; pSG5-HMG-I; 5 µg] and pBABE-puro (1 µg) for puromycin resistance with the use of lipofectin as described by the manufacturer (Life Technologies, Inc.; Ref. 22 ). These two plasmids are kind gifts from Dr. Linda M. S. Resar (The Johns Hopkins University, Baltimore, MD), and more details are described by Wood et al. (22) . Transfected cells were selected in medium containing puromycin (0.60 µg/ml), and single clones were isolated using cloning cylinders. Cloned cells were maintained in medium containing puromycin (0.60 µg/ml), and the overexpression of HMGI(Y) was confirmed by immunoblot on whole cell lysate. The untransfected (parental) LNCaP was passaged continuously in parallel with the transfectants.

Immunofluorescence.
After the fixation in methanol and blocking, cultured cells were incubated with polyclonal anti-HMGI(Y) antibody (N19; Santa Cruz Biotechnology) at a dilution of 1:100 and then with fluorescein-conjugated donkey antigoat IgG (Santa Cruz Biotechnology) at a dilution of 1:200. The samples were observed with a fluorescence microscopy.

Protein Preparation.
Whole cell lysate was prepared from each cell line in RIPA buffer [1x PBS(-), 1% NP40, 0.5% sodium deoxycholate, and 0.1% SDS] as described by the manufacturer (Santa Cruz Biotechnology). Nuclear matrix protein was extracted as reported (12) . Protein concentration was measured using Coomassie® Plus Protein Assay reagent (Pierce).

Immunoblot.
Protein samples were separated in 18% or 4–15% polyacrylamide gel (Bio-Rad) and transferred to a nitrocellulose membrane. The nitrocellulose membrane was probed as described by the manufacturer (Santa Cruz Biotechnology) with anti-HMGI(Y) antibody (N19; Santa Cruz Biotechnology) at a dilution of 1:200 and then with horseradish peroxidase-conjugated donkey antigoat IgG (Santa Cruz Biotechnology) at a dilution of 1:10,000. The signal was detected with an enhanced chemiluminescence kit (Amersham Pharmacia Biotech). The monoclonal antibody against ß-actin (clone AC15; Sigma Chemical Co.) was used at a dilution of 1:5000 to control sample loading of whole cell lysate. The blots were scanned by Personal Densitometer SI (Molecular Dynamics) and quantified by Image Quant 5.0 (Molecular Dynamics).

cDNA Microarray Assay.
Control LNCaP cells transfected with empty vector (pSG5) and LNCaP cells transfected with pSG5-HMG-I were compared by Atlas Human1.2 Array (Clontech).

Spectral Karyotyping.
SKY analysis was performed on air-dried slides made from standard cytogenetic harvests. The slides were hybridized according to the protocol supplied by the probe manufacturer (Applied Spectral Imaging, Inc., Carlsbad, CA). The SKY probe is a mixture of whole-chromosome paint probes for each chromosome, combinatorially labeled with five fluorochromes. Metaphase images were acquired using a standard epifluorescence microscope equipped with the ASI SpectraCube SD200 system. 4',6-Diamidino-2-phenylindole-counterstained images were captured and inverted by SkyView software (ASI, Carlsbad, CA) to provide enhanced banding. Ten metaphases were captured and analyzed for each cell line or clone at each time point. Chromosome abnormalities were described according to International System for Human Cytogenetic Nomenclature (ISCN 1995) guidelines. The same structural aberration or chromosome gain was required to be seen in at least two cells, and whole chromosome losses were required in at least three cells to define a cytogenetic subclone.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
The level of HMGI(Y) protein expression was examined by applying immunoblots on whole cell lysate obtained from three prostate cancer cell lines (LNCaP, DU145, and PC-3) that exhibited large differences in their levels of DNA rearrangement and chromosomal abnormalities (21) . The measured level of HMGI(Y) protein correlated strongly with the reported (21) chromosomal structural aberrations (Fig. 1)Citation . The levels of HMGI(Y) protein increased from 1- to 4.1-fold, whereas the relative structural chromosome changes similarly increased from 1- to 3.8-fold.



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  		Fig. 1. Correlation between the level of HMGI(Y) protein and structural chromosomal aberrations in human prostate cancer cell lines. Relative HMGI(Y) is determined in the whole cell lysate as the intensity of the band of HMGI(Y) divided by that of ß-actin. Structural chromosomal aberrations/diploid cells were reported by Behesti et al. (21) .

 
HMGI(Y) is a nuclear protein, the location to the nucleus of which is demonstrated by immunohistochemistry in Fig. 2ACitation . The intensity of the nuclear staining was weakest in LNCaP, moderate in DU145, and strongest in PC-3 and was similar to the whole cell lysate protein expression of HMGI(Y) shown in Fig. 1Citation . The nuclear matrix portion of the nucleus was extracted and examined by immunoblotting using the polyclonal anti-HMGI(Y) antibody. The HMGI(Y) protein band in the nuclear matrix fraction migrated at Mr 22,000 (Fig. 2B)Citation . As reported by others, the isolated protein did not resolve clearly into HMG-I and HMG-Y isoforms, which derive from a single gene by alternate splicing that removes 11 amino acids, yielding the shorter (Y) isoform. Together, they are referred to as HMGI(Y). The assay of HMGI(Y) protein levels in the nuclear matrix fraction protein from LNCaP, DU145, and PC-3 gave the relative ratio of 1:3.4:5.5, respectively, which is consistent with the order of the levels in the whole cell lysates (Fig. 1)Citation and with the results of the immunofluorescence staining (Fig. 2A)Citation .



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  		Fig. 2. The subcellular localization of HMGI(Y) in human prostate cancer cell lines. A. immunofluorescence shows the nuclear localization of HMGI(Y) in LNCaP, DU145, and PC-3 with different intensity. B, the immunoblot shows that HMGI(Y) is expressed in the nuclear matrix. Twenty µg of nuclear matrix protein were applied to each lane. The gel was stained with Coomassie Brilliant Blue to control for sample loading. HMGI(Y) is detected as a Mr 22,000 protein in nuclear matrix fraction. Relative expression level of HMGI(Y) is shown below each lane.

 
The LNCaP and PC-3 cells were karyotyped and compared using G-banding analysis and the SKY technique that differentially colors each of the 24 chromosomes. The LNCaP cells demonstrated four reciprocal, balanced translocations [t(1;15) x 2; t(4;6) x 2; t(6;16) x 2 and t(6;10) x 2, followed by t(4;der(6)), where the observed del(10) in Fig. 3Citation is the remainder of a balanced translocation below the resolution level of SKY or G-banding] and no unbalanced translocation, and this confirms the reports of others (Refs. 20 , 21 ; Figs. 3Citation and 5Citation ). In contrast, in a direct comparative study, the PC-3 cells were karyotyped by G-banding and SKY and demonstrated no balanced translocations but instead had an average of 31 clonal unbalanced translocations/cell (Fig. 3)Citation . PC-3 is suggested as a model for the genetically unstable form of prostate cancer and LNCaP as a model for the genetically more stable form.



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  		Fig. 3. Comparison of types of chromosomal translocations between LNCaP and PC-3. A, SKY of LNCaP shows rearranged chromosomes resulting from four balanced translocations (white closed circle). der(10)t(6;10) is shown as del(10) because of the resolution level of SKY. All of the chromosomes with translocation in LNCaP have two copies. B, SKY of PC-3 shows 31 unbalanced translocations (yellow arrowheads). der(3) and der(12) in PC-3 have two copies of chromosomes with translocations.

 


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  		Fig. 5. Comparison of individual chromosomes after SKY classification from LNCaP parental (Control), transfectant clone 6 (Empty Vector), and transfectant clone 10 (HMGI vector). All of the translocations seen commonly in all of the three lines are balanced translocations and are labeled as common; these result in a rearrangement of DNA but no net loss or gain. New unbalanced translocations, observed in addition to the normal homologous chromosomes, are illustrated. These result in a net loss or/and gain of the two involved chromosomes. Most new unbalanced rearrangements are seen in only one cell [exceptions: der(11) in all cells of clone 6; and der(22) in two cells of clone 6], indicating the continuing generation of new rearrangements rather than the expansion of a single rearranged subclone. Note: The short chromosome 10 resulting from t(6;10) has been interpreted by ourselves and others as a deleted chromosome 10; however, a recent fluorescence in situ hybridization study has detected a small amount of material deriving from chromosome 6 on the der(10); thus, this is a balanced t(6;10) (Ref. 33 ). One copy of the der(6) has been lost in all of the cells examined by us, although two copies have been reported (20 , 21) .

 
Correlations of HMGI(Y) expression with unbalanced rearrangements of chromosomes are suggestive, but cause and effect are not demonstrated. Toward this end, we then transfected full-length mouse HMG-I vector into LNCaP cells to determine whether overexpression could induce genetic instability, observable as an increase in the level of the unbalanced chromosomal translocations. Stable monoclonal cells were established, and the level of expressed HMGI(Y) was assayed by the immunoblots of the whole cell lysate. There was no difference in the level of HMGI(Y) protein expression between control LNCaP cells transfected with the empty control vector (pSG5) and the untransfected parental LNCaP (Fig. 4)Citation . In contrast, a >3-fold increase in HMGI(Y) expression was observed in LNCaP transfected with HMG-I vector (Fig. 4)Citation . After 4 months of continuous culture with 20 passages and again at 8 months, 10 metaphase spreads of each stable cell line were analyzed by G-banding and SKY technique, and their new unique unbalanced chromosomal translocations were counted. There were 12 new unique unbalanced translocations in 10 of 20 LNCaP cells transfected with the HMG-I vector, whereas only two new unique unbalanced translocations were observed in 3 of 20 LNCaP cells transfected with the empty control vector. No new rearrangements were seen in the parental LNCaP (Fig. 5)Citation . Fig. 4Citation indicates that the level of expressed HMGI(Y) and the number of induced unbalanced translocations are closely correlated.



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  		Fig. 4. Correlation between the level of expressed HMGI(Y) and the number of new unique unbalanced chromosomal translocations in LNCaP transfectants. Relative HMGI(Y) is determined as in Fig. 1Citation . Using G-banding and SKY new and unique unbalanced chromosomal translocations were determined on 20 metaphase spreads in each cell line from 4 to 8 months after transfection.

 
Preliminary microarray DNA expression comparisons between control LNCaP transfected with the empty vector and LNCaP transfected with HMG-I demonstrated no significant differences beyond 1.7-fold change in any of the following genes that might be involved in DNA rearrangements: Ku70, Ku80, ligase-IV, topoisomerase I, and topoisomerase II. Indeed, there were only marginal changes in any of the 1176 genes tested. This indicates that HMGI(Y) does not induce a broad increase in the gene expression profile. However, this limited analysis of genes does not eliminate the HMGI(Y) induction of other critical genes that could be involved in DNA rearrangements.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
HMGI(Y) is expressed in embryonic tissues and is usually down-regulated in mature adult cells. In contrast, HMGI(Y) is re-expressed in various cancer cells of human and animal tumors (23) and has been proposed to be associated with the more aggressive and metastatic features of many cancers (18 , 24, 25, 26) . Transfections of HMGI(Y) into the nonmalignant fibroblast has been reported to transform it and to increase its metastatic potential (22) . In human prostate cancer, increased expression of HMGI(Y) has been associated with higher Gleason grades (26) that reflect more aggressive pathology. Metastatic lesions in prostate cancer are usually associated with higher chromosomal instability (27) .

Other HMG proteins, not related to HMGI(Y) and expressed from other genes, such as HMG1 and HMG2, have been implicated in recombinations within the same chromosome producing the DNA rearrangements of the genes associated with immunoglobulin diversity at the V(D)J junction (28) . Recombination misdirected to inappropriate targets could generate the balanced translocations seen in lymphomas. In comparison, we would suggest a different mechanism for generating unbalanced rearrangements. HMGI(Y) may form complexes facilitating DNA cross-overs. Models of the DNA architecture at sites of homologous rearrangements have included four-way junctions. Here the double helix in each of the two DNA strands is pulled apart to form right-angle bends that hybridize to the opposite strand, forming a four-way junction in the shape of a cross (16) . In vitro, these DNA four-way junctions have been reported to bind to either HMGI(Y), histone H1, or HMG1 (17) . Of these three binding proteins, HMGI(Y) showed the highest affinity to form the four-way junctions (17) . In addition, when these three proteins were tested in vitro for their ability to enhance the integration of HIV cDNA into host DNA, strong enhancing ability was observed only with HMGI(Y) but not with either histone H1 or HMG1; and, in vitro preintegration complexes formed only with HMGI(Y) (29) . This reported ability of HMGI(Y) to alter DNA structure and its relationship proposed for viral integration, a form of heterologous recombination, also led us to select HMGI(Y) as a possible candidate protein for DNA rearrangement mechanisms in cancer cells. HMGI(Y) may be involved in both viral insertion and DNA rearrangement through a similar mechanism of binding to and stabilizing of four-way junction-like intermediates. These DNA cross-over structures are formed by four single strands of DNA originating by pulling apart two double strands of DNA.

HMGI(Y) is a candidate for stabilizing and directing DNA architecture, but an integrating activity would also be required for DNA rearrangement, and topoisomerase II has been reported to function in such a role (30 , 31) . It has been reported that dysfunctional DNA loop attachment to the nuclear matrix and topoisomerase II activity at the MARS may produce illegitimate recombination (30) . Indeed, when exogenous circular DNA is added in vitro to the nuclear matrix, it catenates the plasmids into a network (31) . These mechanisms have been reviewed by Razin (7) . HMGI(Y) has been reported to be colocalized with topoisomerase II (9 , 10) on the nuclear matrix that is attached to the base of the DNA loop domains. Topoisomerase II is located in close proximity to the base of the loop at the fixed sites of DNA replication (14) . Single-strand DNA generated at this site by replication, transcription, and base-unpairing are all possible sites for DNA rearrangement or recombination, because four-way junction-like intermediate cross-over structures are formed after single-strand DNA invades the other double-strand DNA. The colocalization of topoisomerase II with HMGI(Y) (7 , 9 , 10) may also enhance formation of this intermediate cross-over and exchange of single-strand DNA by twisting and nicking of double-strand DNA (32) . Reported binding of HMGI(Y) to the MARS of DNA that are attached to the matrix in the area of the base unpairing region would also be a desirable feature of chromatin changes that could be involved in the formation of such structures (18) . In summary, the ability of HMGI(Y) to bend DNA and to bind to the A-T-rich region of the repetitive sequences and base unpairing regions of MARS, as well as its affinity for four-way junctions, and its proximity to topoisomerase II should all enhance the architectural ability of HMGI(Y) to function as a critical element in chromosomal rearrangements.

It is recognized that unbalanced chromosomal translocations are more commonly found in solid tumors and that the exact mechanism of their formation may be a complex process. In this study, we demonstrated that in vitro overexpressing of HMGI(Y) using transfection techniques induced increased unbalanced chromosomal translocations in an otherwise chromosomal stable human prostate cancer cell line. Even after 4–8 months in culture, continuing generation of a heterogeneous population was observed. We suggest that the findings reported in this study enhance the candidacy of HMGI(Y) as an important possible element in the process of unbalanced chromosomal rearrangements.


   ACKNOWLEDGMENTS
 
We thank Laura A. Morsberger, J. Ryan Coffman, and Donald Vindivich for technical assistance and preparation of photos and graphs. We thank Vivian Bailey for preparing the manuscript. We thank Dr. Linda M. S. Resar (The Johns Hopkins University, Baltimore, MD) for providing us with expression vector of mouse HMG-I.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This study was supported by NIH Grants NCI CA-58236, NIDDK-22000, and NCI CA-15416. Back

2 To whom requests for reprints should be addressed, at Department of Urology, The Johns Hopkins Hospital, Marburg 121, 600 North Wolfe Street, Baltimore, MD 21287. Phone: (410) 955-2517; Fax: (410) 502-9336; E-mail: vbailey{at}jhmi.edu Back

3 The abbreviations used are: MARS, matrix attachment regions; HMGI(Y), high mobility group protein I(Y); FISH, fluorescence in situ hybridization; SKY, spectral karyotyping. Back

Received 10/15/01. Accepted 12/11/01.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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