HP1β suppresses metastasis of human cancer cells by decreasing the expression and activation of MMP2

  • Authors:
    • Sang Ah Yi
    • Hyun‑Wook Ryu
    • Dong Hoon Lee
    • Jeung‑Whan Han
    • So Hee Kwon
  • View Affiliations

  • Published online on: September 9, 2014     https://doi.org/10.3892/ijo.2014.2646
  • Pages: 2541-2548
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Abstract

Heterochromatin protein 1 (HP1) is an epigenetic modifier of gene regulation and chromatin packing via binding to trimethylated histone H3 lysine 9 (H3K9). HP1 plays an important role in gene activation as well as gene repression in heterochromatin and euchromatin. However, the role of individual HP1 proteins in human diseases remains elusive. Here, we show that HP1β negatively regulates the expression and activation of matrix metallopeptidase (MMP)2, which mediates cancer metastasis by destructing type Ⅳ collagen. Reduced HP1β expression correlates with the increased level of pro‑ and active‑MMP2 in colon cancer cells. Consistently, HP1β knockdown (KD) increased and HP1β overexpression decreased the mRNA level of MMP2 and membrane type 1 metallopeptidase (MT1‑MMP). Furthermore, cancer cells overexpressing HP1β showed impaired migratory ability, whereas HP1β‑deleted cancer cells had increased migration. HP1β negatively regulates MMP2 expression in a transcriptional level and prevents MMP2 activation through reducing the expression of MT1‑MMP. These findings shed new light on HP1β as a molecular regulator and an efficient therapeutic target of metastatic cancer.

Introduction

Heterochromatin protein 1 (HP1) is a histone code reader which specifically recognizes and binds to methylated H3 lysine 9 (H3K9) (1). Through its activities in DNA and its interacting proteins, the mammalian HP1 family plays a critical role in a variety of cellular processes including centromere stability, telomere stability, regulation of gene expression, DNA repair, cellular senescence and cancer progression (24). Three human HP1 homologs (HP1α, HP1β and HP1γ) contain two conserved domains, which are separated by a flexible hinge region: a chromodomain (CD) interacting with methylated H3K9 and a chromoshadow domain (CSD) interacting with the PxVxL motif of its partner (5). HP1 homologs are known to exhibit different subnuclear localizations in interphase: HP1α and HP1β are centromeric while HP1γ is located in both euchromatic and heterochromatic regions (3,6,7). As might be expected given their name and localization, HP1 in mice and human represses transcription and suppresses tumor through formation of multimolecular complex with transcriptional corepressor TIF1β, histone methyltransferase SETDB1 and NuRD-histone deacetylase complex (8). However, it has been recently reported that HP1 may work at euchromatic regions and as a positive regulator in gene expression (5,9,10).

Several reports show that expression of HP1 is changed in various tumor tissues compared with normal tissues. In papillary thyroid carcinomas and embryonal brain tumor, the mRNA level of HP1α was decreased (11,12), which makes HP1α a predictor in these cancers. HP1α expression is also decreased in invasive/metastatic breast cancer tissue and HP1α knockdown (KD) reduces the invasion rate of metastatic breast cancer cells (13,14), suggesting HP1α is a metastatic suppressor. In addition to HP1α, reduction of HP1β expression is correlated with invasive activity in human melanoma cells (15). Different from these beneficial effects, the three homologs of HP1 were highly expressed in patients with acute myeloid leukemia and chronic myeloid leukemia (16). However, the molecular mechanism whereby the expression of HP1 proteins is regulated in cancer is not well understood.

Matrix metallopeptidases (MMPs) are a family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases capable of degrading almost all components of ECM (17). MMPs are important not only in normal, physiological and biological processes such as embryogenesis, normal tissue remodeling, wound healing and angiogenesis but also in diseases such as arthritis and cancer (18). Expression and activation of MMP are increased in almost all human cancers compared to normal tissue. Indeed, MMPs play important roles in carcinogenesis as well as invasion and metastasis (19). MMPs can regulate cell migration by removing sites of adhesion, exposing new sites, cleaving cell-cell or cell-matrix receptors and releasing chemo attractants from ECM (20). MMP2/14 degrades laminin 5 and reveals a cryptic site that triggers motility (19). In addition to migration, MMP2/9 are localized in invadopodia and promote invasion by degrading type IV collagen of basement membrane (21,22).

To understand this issue, we have identified the expression patterns of HP1 in various cancer cells. We show that HP1β inhibits de novo expression and activation of MMP2 through the control of mRNA level of MMP2 and membrane type 1 metallopeptidase (MT1-MMP). Collectively, this study is the first to elucidate the functional relationship of HP1β and MMP2 in cancer metastasis.

Materials and methods

Cell culture and transfection

Human cancer cell lines were cultured according to the instructions from ATCC and were maintained under a fully humidified atmosphere of 95% air and 5% CO2 at 37°C. Cancer cells were grown to 70% confluence in plates, the cells were transfected with siRNA or GFP-tagged vectors using Lipofectamine 2000 reagent, according to manufacturer’s protocol (Invitrogen Life Technologies, Carlsbad, CA, USA). After incubation for 48 h, mRNAs and proteins were extracted from the cells. The sequences of siRNAs targeting HP1 genes were: HP1α, 5′-GUUCCAGUCCUCUCUCAAAGC-3′ and 5′-GCUUUG AGAGAGGACUGGAAC-3′; HP1β, 5′-GACUCCAGUGGA GAGCUCAUG-3′ and 5′-CAUGAGCUCUCCACUGGA GUC-3′; HP1γ, 5′-AUUCUUCAGGCUCUGCCUC-3′ and 5′-GAGGCAGAGCCUGAAGAAU-3′ (HP1α HP1β, and HP1γ primers were described previously) (23).

Western blotting

Immunoblotting was performed as previously described (24). Cell lysates were prepared using lysis buffer supplemented with protease and phosphatase inhibitors (Thermo Scientific Pierce, Rockford, IL, USA). Protein concentrations were quantified according to the BCA Protein Assay kit (Thermo Scientific Pierce, Rockford, IL, USA).

RT-PCR and quantitative real-time PCR (qRT-PCR)

Total RNA was extracted using easy-Blue reagent (Intron Biotechnology, Seoul, Korea) and 1 μg of RNA with oligo dT primers was subjected to reverse transcription using the ImProm-II™ Reverse Transcription system (Promega Corporation, Madison, WI, USA). cDNA was amplified using Super Premix Sapphire PCR master mix (Mbiotech, Inc., Seoul, Korea). qRT-PCR was performed with the KAPA™ SYBR® FAST qPCR (Kapa Biosystems, Inc., Wilmington, MA, USA) using CFX96™ or Chromo4™ real-time PCR Detector (Bio-Rad, Hercules, CA, USA). Relative levels of mRNA were normalized to the values of GAPDH mRNA for each reaction. Primer sequences used for PCR were: MMP2, 5′-ACCAGCTGGCCTAGTGATGATG-3′ and 5′-GGCTT CCGCATGGTCTCGATG-3′; MT1-MMP, 5′-GGAATAAC CAAGTGATGGATGG-3′ and 5′-TTGTTTCCACGGAAGA AGTAGG-3′; tissue inhibitor of metallopeptidase (TIMP)2, 5′-GCGGTCAGTGAGAAGGAAGTGG-3′ and 5′-CTTGCA CTCGCAGCCCATCTG-3′; GAPDH, 5′-GAGTCAACGGAT TTGGTCGT-3′ and 5′-TTGATTTTGGAGGGATCTCG-3′.

Migration assay

Human cancer cells grown in 6-well plates were scratched with a yellow pipette tip to form a thin wound. Microscope images were observed immediately and 48 h after the scratch.

Results

Analysis of HP1 expression in human cancer cell lines

To investigate the potential role of HP1 in human cancer, we first examined the expression levels of the three HP1 proteins in diverse human cancer cell lines, which originated from eight different organs. The cell lines we used are indicated in Table I. HP1α and HP1β were more highly expressed in MCF7, a non-invasive breast cancer cell line, than the two invasive breast cancer cell lines (Fig. 1A). HP1γ was uniquely repressed and histone H3 lysine 9 methylation (H3K9me3) was dramatically increased in only MDA-MB-231, invasive breast cancer cells. Colon cancer cells are sorted according to the Dukes grade. Among the five colon cancer cell lines, only SW-480 is classified as Dukes grade B, which has invasion through the bowel wall, but does not involve lymph nodes. The expression levels of HP1α, β and γ were all high in SW-480 (Fig. 1B). The other colon cancer cell lines, which are classified as Dukes grade C, involving invasion of the lymph nodes, expressed high levels of all three HP1 proteins. In IMR90, a normal lung cell line, the three HP1 proteins and H3K9me3 were all suppressed compared to the two lung cancer cell lines (Fig. 1C). On the other hand, the HP1 proteins and H3K9me3 were more highly expressed in 293T/17, normal kidney cell line, than ACHN, renal cell adenocarcinoma (Fig. 1D). These results suggest that HP1 proteins are related to tumor progression in lung, but tumor suppression in kidney. In the liver cancer cell lines, HP1α and HP1γ were more highly expressed in HepG2 while HP1β and H3K9me3 were more highly expressed in SK-HEP1 (Fig. 1E). In the ovarian cancer cell lines, the three HP1 proteins showed similar expression patterns, but H3K9me3 showed an opposite pattern (Fig. 1F). In leukemia and osteosarcoma cell lines, HP1γ and H3K9me3 were expressed in the same pattern (Fig. 1G and H). Taken together, these results show that the expression patterns of the HP1 proteins vary in different cancer types and degree of invasiveness (Table I).

Table I

The human cancer cell lines investigated.

Table I

The human cancer cell lines investigated.

OrganCell lineTumor type/stageHP1αHP1βHP1γ
BreastMDA-MB-468Malignant adenocarcinoma−−+
MDA-MB-231Malignant adenocarcinoma−−−−
MCF7Adenocarcinoma+++
ColonSW-480Colorectal adenocarcinoma/Duke’s grade B+++
HCT-116Colorectal carcinoma/Duke’s grade C+++
DLD-1Colorectal adenocarcinoma/Duke’s grade C−−−−−−
HCT-15Colorectal adenocarcinoma/Duke’s grade C
LoVoColorectal adenocarcinoma/Duke’s grade C+
LungH1299Carcinoma+++−−
A549Carcinoma+
IMR90Normal fibroblast−−−−
Kidney293T/17Normal epithelial cell++
ACHNRenal cell adenocarcinoma−−−−
LiverHepG2Hepatocellular carcinoma++
SK-HEP1Adenocarcinoma+
OvarianSKOV3Adenocarcinoma
OVCAR3Adenocarcinoma++++++
TOV21GMalignant adenocarcinoma/grade 3, Stage III+++
LymphoblastK562Chronic myelogenous leukemia−−+
JurkatAcute T cell leukemia+++
BoneU2OSOsteosarcoma
SJSA-1Multipotential osteosarcoma++−−
Inverse correlation of MMP2 and HP1β in colon cancer cells

Although to different extents, the three HP1 proteins were highly expressed in colon cancer cell lines. To determine whether HP1 and MMP2 are involved in colorectal cancer, we first analyzed the expression pattern of MMP2 and HP1 proteins in six colon cancer cell lines. MMP2, which degrades the basic component of cellular membrane, is regarded as a leading molecule in the metastatic process of cancer development (17,19). Inactive pro-MMP2 is 70 kDa and active-MMP2, derived from cleavage of pro-MMP2 is smaller (35–50 kDa). Among the members of HP1 family, HP1β showed a reverse expression pattern with active-MMP2 (Fig. 2A). Using ImageJ program, we quantified the expression level of active-MMP2 and HP1s displayed in Fig. 2A and assessed the correlation between the values. We confirmed a strong correlation between active-MMP2 and HP1β through the coefficient of determination (R2=0.5202) (Fig. 2B, middle). HP1α showed a weak correlation with active-MMP2, as R2 is 0.1066 (Fig. 2B, left) and HP1γ had no correlation with active-MMP2 (Fig. 2B, right). These data suggest the possibility of a biological relationship between HP1β and MMP2.

HP1β negatively regulates the expression and activation of MMP2 protein

To investigate whether HP1β has influence on the MMP2 protein level, we transfected GFP-empty vector or GFP-tagged HP1 vectors into colon cancer cell line, HCT-15, which showed a weak HP1β signal. Overexpression of HP1β in HCT-15 cells resulted in reduction of pro-MMP2 as well as active-MMP2 (Fig. 3A). In OVCAR3, an ovarian cancer cell line, overexpressing HP1β caused a reduction of pro-MMP2, but not active-MMP2 (Fig. 3B). Similarly, only the pro-MMP2 level in HeLa cells was decreased depending on the amounts of ectopically expressed HP1β (Fig. 3C). We cannot exclude the possibility that, because the high basal expressions of HP1β is enough to saturate the active-MMP2 level, exogenously expressed HP1β results in no significant change in the active-MMP2 level in OVCAR3 and HeLa cells (Fig. 3E and F). Therefore, we next examined the MMP2 level in HP1β-depleted cells. In HT-29, a colon cancer cell line, KD of HP1β promoted both pro- and active-MMP2 (Fig. 3D). Increase of pro-MMP2 and active-MMP2 levels following HP1β KD, was observed in OVCAR3 and HeLa cells (Fig. 3G and H). These effects were also observed in HP1α but to a lesser extent (Fig. 3A–D and G). Thus, these results suggest that HP1β is a major regulator of MMP2 expression and activation and HP1α is a minor regulator.

HP1β regulates the mRNA expression of MMP2 and MT1-MMP

To examine whether HP1β regulates MMP2 expression at the transcription level, we measured the mRNA level of MMP2 in HP1β-deleted cells. The mRNA level of the MMP2 gene increased 1.5-fold, following KD of HP1β in HCT-15 cells (Fig. 4A). However, considering that HCT-15 cells express very low basal level of HP1β, this is regarded as a significant change. In OVCAR3 and HeLa cells, which express a high basal level of HP1β, the mRNA level of MMP2 increased >5-fold following KD of HP1β (Fig. 4B and C).

The activation of MMP2 is triggered by the cleavage of pro-MMP2 by MT1-MMP, which is influenced by the level of TIMP. TIMP2 binds to the active site of MT1-MMP and this complex acts as a receptor for pro-MMP2. Then, the free MT1-MMP cleaves the propeptide of pro-MMP2, leading to the intermediate stage. Through further autocatalytic proteolysis, fully active MMP2 is generated (Fig. 5A) (25). However, when the TIMP2 level is high enough to saturate all MT1-MMP, cleavage of pro-MMP2 is impossible preventing MMP2 activation (Fig. 5B). We found that active-MMP2 as well as pro-MMP2 was changed by HP1β (Figs. 3 and 4). Thus, we examined whether the mRNA levels of MT1-MMP and TIMP2 are regulated by HP1β. The mRNA levels of MMP2 and MT1-MMP decreased following overexpression of HP1β in HCT-15 and OVCAR3 cells, while the level of TIMP2 did not significantly change (Fig. 5C and D). Consistent with this result, KD of HP1β promotes the mRNA level of MMP2 and MT1-MMP in both cell lines (Fig. 5E and F).

HP1β inhibits migration of human cancer cells

Recent studies of breast cancer cells revealed an inverse correlation between HP1α expression and tumor cell invasiveness (13,14). We therefore investigated whether tumor cell motility is regulated by all three HP1 protein or in an HP1 isoform-specific manner. To do this, we assessed the migratory ability of HeLa cells transfected with GFP-tagged vectors or siRNA following scratch with a yellow tip. Overexpression of HP1β markedly decreased the migration rate of HeLa cells (Fig. 6A), while KD of HP1β promoted migration of HeLa cells (Fig. 6B). Interestingly, overexpression or KD of HP1α resulted in the similar, but lesser effects, on the migration rate compared to HP1β. In contrast, modulating the expression of HP1γ did not affect the migration. Thus, it suggests that HP1β and HP1α, but not HP1γ, are responsible for cancer metastasis.

Discussion

The HP1 family of proteins was identified >25 years ago (26), but the common or divergent functions of the three homologs remain unclear. There are several indications that the three mammalian HP1 homologs, HP1α, β and γ, may not fulfil identical functions. First, they show differences in cellular distribution. HP1α marks strongly in the pericentric heterochromatin, whereas HP1γ shows less specificity for these regions (3,6,7). Second, despite their high similarity in structure and function, the three HP1 homologs are not always present together and can interact with different binding partners (3). Finally, distinct post-translational modifications on an individual HP1 homolog (6,27) may further diversify their functions. Here, we show that in human cells, HP1β has unique properties in cancer development, which are not shared by HP1α and γ. First, we find opposite expression patterns of HP1β and MMP2, which promotes metastasis in cancer. Second, we reveal that overexpression of HP1β reduces protein levels of both pro-MMP2 and active-MMP2; this is mediated by suppressed mRNA level of MMP2 and MT1-MMP, which are required for the activation of MMP2. Consistently, KD of HP1β increases protein levels of pro-MMP2 and active-MMP2. mRNA level of MMP2 and MT1-MMP are also increased by HP1β KD. Furthermore, we demonstrate that overexpression of HP1β represses the migration of human cancer cell and KD of HP1β promotes cell migration.

The links between HP1 proteins and tumorigenesis have emerged. In vitro studies of HP1 expression in cancer have suggested that these proteins protect against tumor cell aggressiveness and invasiveness. HP1α is overexpressed in carcinomas and the expression level correlates with clinical data and disease outcome (28). This has been most convincingly shown in breast cancer cell lines (13,14). Downregulation of the HP1α protein is linked to a higher invasive potential of cancer cells (3,11,13,29). HP1α downregulation has been observed in most highly invasive and metastatic breast cancer cells versus non-metastatic cells (13,14,29). Decreasing the HP1α expression in non-invasive MCF-7 cells enhanced the invasive potential; increasing the HP1α expression in metastatic MDA-MB-231 cells decreased the invasive potential (30). In this study, we show that HP1β overexpression causes impaired migratory ability, whereas HP1β KD results in increased migration. Moreover, our findings reveal the molecular mechanism by which HP1β regulates cancer migration and metastasis. HP1β negatively regulates MMP2 expression at the transcriptional level and prevents MMP2 activation by reducing the expression of MT1-MMP. In line with this finding, decreased HP1β expression is associated with melanoma oncogenesis and high invasiveness in human melanoma cells (15). Consequently, because HP1α and HP1β have been shown to attenuate metastasis in cancer cells, it may be, given the data presented here, that HP1 is a suppressor of cell migration and metastasis. Interestingly, the reverse pattern of euchromatic HP1γ and H3K9me3 was observed in different cancer cells including breast, ovarian, lung, and liver cancer cells (Fig. 1). This result supports the hypothesis that HP1γ might regulate certain cancer-associated genes via a different epigenetic mechanism, not shared by HP1α and β.

Taken together, our results elucidate the role of HP1β as a key regulator of cancer metastasis by reducing both expression and activation of MMP2, which is mediated by altered mRNA levels of MMP2 and MT1-MMP. These findings suggest the epigenetic regulation of MMP2 by HP1β and provide the mechanistic rationale for the targeting of HP1β to relieve cancer metastasis.

Acknowledgements

This research was supported by Medical Research Center programs (2012-0009849) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012013998).

Abbreviations:

ECM

extracellular matrix

H3K9me

histone H3 lysine 9 methylation

HP1

heterochromatin protein 1

KD

knockdown

MMP

matrix metallopeptidase

MT1-MMP

membrane type 1 matrix metallopeptidase

TIMP

tissue inhibitor of metallopeptidase

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December-2014
Volume 45 Issue 6

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Yi SA, Ryu HW, Lee DH, Han JW and Kwon SH: HP1β suppresses metastasis of human cancer cells by decreasing the expression and activation of MMP2. Int J Oncol 45: 2541-2548, 2014
APA
Yi, S.A., Ryu, H., Lee, D.H., Han, J., & Kwon, S.H. (2014). HP1β suppresses metastasis of human cancer cells by decreasing the expression and activation of MMP2. International Journal of Oncology, 45, 2541-2548. https://doi.org/10.3892/ijo.2014.2646
MLA
Yi, S. A., Ryu, H., Lee, D. H., Han, J., Kwon, S. H."HP1β suppresses metastasis of human cancer cells by decreasing the expression and activation of MMP2". International Journal of Oncology 45.6 (2014): 2541-2548.
Chicago
Yi, S. A., Ryu, H., Lee, D. H., Han, J., Kwon, S. H."HP1β suppresses metastasis of human cancer cells by decreasing the expression and activation of MMP2". International Journal of Oncology 45, no. 6 (2014): 2541-2548. https://doi.org/10.3892/ijo.2014.2646