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Metastasis-associated Protein 1 Drives Tumor Cell Migration and Invasion through Transcriptional Repression of RING Finger Protein 144A*

Open AccessPublished:February 17, 2012DOI:https://doi.org/10.1074/jbc.M111.314088
      Metastasis-associated protein 1 (MTA1), a component of the nucleosome-remodeling and histone deacetylase complex, is widely up-regulated in human cancers and significantly correlated with tumor invasion and metastasis, but the mechanisms involved remain largely unknown. Here, we report that MTA1 transcriptionally represses the expression of RING finger protein 144A (RNF144A), an uncharacterized gene whose protein product possesses potential E3 ubiquitin ligase activity, by recruiting the histone deacetylase 2 (HDAC2) and CCAAT/enhancer-binding protein α (c/EBPα) co-repressor complex onto human RNF144A promoter. Furthermore, an inverse correlation between the expression levels of MTA1 and RNF144A was demonstrated in publicly available breast cancer microarray datasets and the MCF10 breast cancer progression model system. To address functional aspects of MTA1 regulation of RNF144A, we demonstrate that RNF144A is a novel suppressor of cancer migration and invasion, two requisite steps of metastasis in vivo, and knockdown of endogenous RNF144A by small interfering RNAs accelerates the migration and invasion of MTA1-overexpressing cells. These results suggest that RNF144A is partially responsible for MTA1-mediated migration and invasion and that MTA1 overexpression in highly metastatic cancer cells drives cell migration and invasion by, at least in part, interfering with the suppressive function of RNF144A through transcriptional repression of RNF144A expression. Together, these findings provide novel mechanistic insights into regulation of tumor progression and metastasis by MTA1 and highlight a previously unrecognized role of RNF144A in MTA1-driven cancer cell migration and invasion.

      Introduction

      Although advances have been made in tumor diagnosis and therapies, over 90% of cancer-associated mortality is attributable to tumor metastasis (
      • Valastyan S.
      • Weinberg R.A.
      Tumor metastasis: molecular insights and evolving paradigms.
      ,
      • Gupta G.P.
      • Massagué J.
      Cancer metastasis: building a framework.
      ). One of the critical steps during tumor metastasis is tumor cell migration and invasion, which are responsible for the entry of tumor cells into lymphatic and blood vessels as well as the extravasation of tumor cells into the secondary organs (
      • Gupta G.P.
      • Massagué J.
      Cancer metastasis: building a framework.
      ,
      • Steeg P.S.
      Tumor metastasis: mechanistic insights and clinical challenges.
      ). The identification of molecular pathways that contribute to tumor cell motility and invasion is therefore essential for understanding the mechanism of metastasis and for providing new therapeutic targets to treat metastatic cancer (
      • Wang W.
      • Eddy R.
      • Condeelis J.
      The cofilin pathway in breast cancer invasion and metastasis.
      ).
      Accumulating evidence over the past two decades has identified the metastasis-associated protein 1 (MTA1)
      The abbreviations used are:
      MTA1
      metastasis-associated protein 1
      c/EBPα
      CCAAT/enhancer-binding protein α
      EMSA
      electrophoretic mobility shift assay
      HDAC2
      histone deacetylase 2
      MEFs
      mouse embryonic fibroblasts
      qRT-PCR
      quantitative real-time PCR
      RNF144A
      RING finger protein 144A
      siRNA
      small interfering RNA.
      as one of the most important players in the multistep invasion-metastasis cascade (
      • Toh Y.
      • Nicolson G.L.
      The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications.
      ,
      • Kumar R.
      • Wang R.A.
      • Mazumdar A.
      • Talukder A.H.
      • Mandal M.
      • Yang Z.
      • Bagheri-Yarmand R.
      • Sahin A.
      • Hortobagyi G.
      • Adam L.
      • Barnes C.J.
      • Vadlamudi R.K.
      A naturally occurring MTA1 variant sequesters oestrogen receptor-α in the cytoplasm.
      ,
      • Toh Y.
      • Pencil S.D.
      • Nicolson G.L.
      A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses.
      ). Originally, MTA1 was isolated by a differential cDNA library screening using a rat mammary adenocarcinoma metastatic model as an up-regulated gene in highly metastatic cells (
      • Toh Y.
      • Pencil S.D.
      • Nicolson G.L.
      A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses.
      ). Subsequent studies demonstrate that MTA1 is up-regulated in a variety of human cancers, and its expression is closely correlated with tumor invasion and metastasis as well as poor patient survival (
      • Toh Y.
      • Nicolson G.L.
      The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications.
      ,
      • Kumar R.
      • Wang R.A.
      • Bagheri-Yarmand R.
      Emerging roles of MTA family members in human cancers.
      ,
      • Manavathi B.
      • Singh K.
      • Kumar R.
      MTA family of coregulators in nuclear receptor biology and pathology.
      ). In this context, it has been shown that overexpression of MTA1 promotes tumor motility and invasiveness (
      • Mahoney M.G.
      • Simpson A.
      • Jost M.
      • Noé M.
      • Kari C.
      • Pepe D.
      • Choi Y.W.
      • Uitto J.
      • Rodeck U.
      Metastasis-associated protein (MTA)1 enhances migration, invasion, and anchorage-independent survival of immortalized human keratinocytes.
      ,
      • Nicolson G.L.
      • Nawa A.
      • Toh Y.
      • Taniguchi S.
      • Nishimori K.
      • Moustafa A.
      Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation, and nuclear regulation.
      ,
      • Hofer M.D.
      • Menke A.
      • Genze F.
      • Gierschik P.
      • Giehl K.
      Expression of MTA1 promotes motility and invasiveness of PANC-1 pancreatic carcinoma cells.
      ), whereas silencing of MTA1 expression significantly suppresses tumor migration and invasion in various cancer models (
      • Qian H.
      • Yu J.
      • Li Y.
      • Wang H.
      • Song C.
      • Zhang X.
      • Liang X.
      • Fu M.
      • Lin C.
      RNA interference of metastasis-associated gene 1 inhibits metastasis of B16F10 melanoma cells in a C57BL/6 mouse model.
      ,
      • Kai L.
      • Wang J.
      • Ivanovic M.
      • Chung Y.T.
      • Laskin W.B.
      • Schulze-Hoepfner F.
      • Mirochnik Y.
      • Satcher Jr., R.L.
      • Levenson A.S.
      Targeting prostate cancer angiogenesis through metastasis-associated protein 1 (MTA1).
      ,
      • Jiang Q.
      • Zhang H.
      • Zhang P.
      ShRNA-mediated gene silencing of MTA1 influenced on protein expression of ER α, MMP-9, CyclinD1 and invasiveness, proliferation in breast cancer cell lines MDA-MB-231 and MCF-7 in vitro.
      ). Yet, the molecular details of how MTA1 drives tumor migration and invasion, important steps of metastatic cascades, are still largely unknown.
      Recently, in an attempt to uncover novel gene targets and functions of MTA1, we carried out high-throughput microarray-based expression profiling analyses of mouse embryonic fibroblasts (MEFs) under the condition of depletion or overexpression of MTA1 (
      • Ghanta K.S.
      • Li D.Q.
      • Eswaran J.
      • Kumar R.
      Gene profiling of MTA1 identifies novel gene targets and functions.
      ) and discovered that MTA1 modulates the expression of RING finger protein 144A (RNF144A) (also known as KIAA0161, RNF144, or ubiquitin-conjugating enzyme 7-interacting protein 4) in a p53-independent manner (
      • Ghanta K.S.
      • Li D.Q.
      • Eswaran J.
      • Kumar R.
      Gene profiling of MTA1 identifies novel gene targets and functions.
      ,
      • Li D.Q.
      • Pakala S.B.
      • Reddy S.D.
      • Ohshiro K.
      • Peng S.H.
      • Lian Y.
      • Fu S.W.
      • Kumar R.
      Revelation of p53-independent function of MTA1 in DNA damage response via modulation of the p21 WAF1-proliferating cell nuclear antigen pathway.
      ). RNF144A is an uncharacterized gene whose encoding protein contains a RING finger motif that is known to be involved in protein-protein interaction as well as protein ubiquitination and degradation (
      • Joazeiro C.A.
      • Weissman A.M.
      RING finger proteins: mediators of ubiquitin ligase activity.
      ). As many RING finger proteins, such as breast cancer type 1 susceptibility protein (BRCA1; also known as RING finger protein 53), are implicated in cancer development and progression (
      • Lipkowitz S.
      • Weissman A.M.
      RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis.
      ), in the present study we attempted to detail the regulatory mechanism of RNF144A by MTA1 and to investigate the functional implication of the MTA1-RNF144A pathway in cancer progression.
      Here, we provide convincing evidence that MTA1 transcriptionally represses RNF144A expression by recruiting the histone deacetylase 2 (HDAC2) and CCAAT/enhancer-binding protein α (c/EBPα) co-repressor complex onto human RNF144A promoter. Moreover, we demonstrate that RNF144A is a novel suppressor of cancer migration and invasion. Consequently, MTA1 overexpression in highly metastatic tumor cells enhances the ability of cancer cells to migrate and invade by, at least in part, interfering with RNF144A function through transcriptional repression of RNF144A. Thus, the dysregulated MTA1-RNF144A pathway is intimately linked to the migratory and invasive phenotype of cancer cells and may represent a promising target for cancer therapy.

      DISCUSSION

      A critical step in the development of a metastatic tumor is characterized by a gain in the tumor cells' migratory and invasive capabilities (
      • Wicki A.
      • Lehembre F.
      • Wick N.
      • Hantusch B.
      • Kerjaschki D.
      • Christofori G.
      Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton.
      ). In the present study, we investigated the molecular mechanism of transcriptional regulation of RNF144A expression by MTA1 and its attributed functions in cancer migration and invasion, hallmarks of tumor metastasis in vivo. First, we made a systematic attempt to understand the correlation between the expression levels of MTA1 and RNF144A in breast cancer microarray data sets and a breast cancer model system (FIGURE 1, FIGURE 2). Next, we further demonstrated a reverse correlation between MTA1 and RNF144A at the level of mRNA and protein expression in both human breast cancer MCF-7 cells and human cervical carcinoma HeLa cells under the condition of knockdown or overexpression of MTA1 (Fig. 3). These results firmly established a negative correlation between the expression levels of MTA1 and RNF144A. On the mechanistic level, substantial evidence showed that MTA1 transcriptionally represses RNF144A expression by recruiting MTA1/HDAC2/c/EBPα co-repressor complex onto human RNF144A promoter (Fig. 8). Although MTA1 has been shown previously to activate and repress gene transcription in the appropriate cellular and genetic context (
      • Manavathi B.
      • Singh K.
      • Kumar R.
      MTA family of coregulators in nuclear receptor biology and pathology.
      ,
      • Ghanta K.S.
      • Li D.Q.
      • Eswaran J.
      • Kumar R.
      Gene profiling of MTA1 identifies novel gene targets and functions.
      ,
      • Manavathi B.
      • Kumar R.
      Metastasis tumor antigens, an emerging family of multifaceted master coregulators.
      ), in this study we provide the molecular details of how MTA1 drives tumor progression through the delicate transcriptional control of its target genes.
      Figure thumbnail gr8
      FIGURE 8Summary of the findings presented in this study. MTA1 promotes tumor progression by, at least in part, interfering with the suppressive function of RNF144A in tumor migration and invasion through transcriptional repression of RNF144A expression via recruiting the MTA1/HDAC2/c/EBPα co-repressor complex onto human RNF144A promoter.
      Another novel finding presented here is that we demonstrate that transcriptional repression of RNF144A by MTA1 is functionally linked to the malignant phenotype of cancer cells. In this context, we discovered that siRNA-mediated knockdown of human RNF144A, which had not previously been implicated in cancer, increased the migration and invasiveness of MCF-7 cells, suggesting that RNF144A is a novel suppressor of tumor migration and invasion (Fig. 7). This novel finding supports the observations that the expression levels of RNA144A are negatively correlated with those of MTA1 in various tumor models (FIGURE 1, FIGURE 2). Although the mechanism by which RNF144A suppresses the migratory and invasive ability of MCF-7 cells is currently unknown, the mechanistic role of other members of the RNF gene family in cancer invasion and metastasis has been documented. For example, RING finger protein 5 (RNF5) has been shown to inhibit cell motility by targeting cytoskeletal protein paxillin ubiquitination and altered localization (
      • Didier C.
      • Broday L.
      • Bhoumik A.
      • Israeli S.
      • Takahashi S.
      • Nakayama K.
      • Thomas S.M.
      • Turner C.E.
      • Henderson S.
      • Sabe H.
      • Ronai Z.
      RNF5, a RING finger protein that regulates cell motility by targeting paxillin ubiquitination and altered localization.
      ). In contrast, RNF13 and RNF55 (also known as proto-oncogene c-Cbl) promote pancreatic cancer and glioma invasion by enhancing the activity of extracellular matrix metallopeptidase-9 (MMP-9) and MMP-2, respectively (
      • Zhang Q.
      • Meng Y.
      • Zhang L.
      • Chen J.
      • Zhu D.
      RNF13: a novel RING-type ubiquitin ligase overexpressed in pancreatic cancer.
      ,
      • Lee H.
      • Tsygankov A.Y.
      c-Cbl regulates glioma invasion through matrix metalloproteinase 2.
      ), which are required for degrading structural extracellular matrix proteins to promote invasion and metastasis (
      • Egeblad M.
      • Werb Z.
      New functions for the matrix metalloproteinases in cancer progression.
      ). Similarly, RNF45 (also known as tumor autocrine motility factor receptor or gp78) promote sarcoma metastasis by targeting the metastasis suppressor KAI1 for degradation (
      • Tsai Y.C.
      • Mendoza A.
      • Mariano J.M.
      • Zhou M.
      • Kostova Z.
      • Chen B.
      • Veenstra T.
      • Hewitt S.M.
      • Helman L.J.
      • Khanna C.
      • Weissman A.M.
      The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation.
      ). Originally, RNF45 was isolated as a membrane glycoprotein from murine melanoma cells and was implicated in cell migration (
      • Nabi I.R.
      • Raz A.
      Cell shape modulation alters glycosylation of a metastatic melanoma cell surface antigen.
      ,
      • Fang S.
      • Ferrone M.
      • Yang C.
      • Jensen J.P.
      • Tiwari S.
      • Weissman A.M.
      The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum.
      ). Subsequent studies identified RNF45 as the tumor autocrine motility factor receptor mediating tumor invasion and metastasis (
      • Fang S.
      • Ferrone M.
      • Yang C.
      • Jensen J.P.
      • Tiwari S.
      • Weissman A.M.
      The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum.
      ,
      • Nabi I.R.
      • Watanabe H.
      • Raz A.
      Autocrine motility factor and its receptor: role in cell locomotion and metastasis.
      ). In addition, expression of RNF188 (also known as HAKAI or CBLL1) also increases epithelial cell invasion (
      • Rodríguez-Rigueiro T.
      • Valladares-Ayerbes M.
      • Haz-Conde M.
      • Aparicio L.A.
      • Figueroa A.
      Hakai reduces cell-substratum adhesion and increases epithelial cell invasion.
      ). Given that many RING finger proteins have intrinsic E3 ligase activities (
      • Joazeiro C.A.
      • Weissman A.M.
      RING finger proteins: mediators of ubiquitin ligase activity.
      ), it is possible that RNF144A exerts its effect on cell migration and invasion through ubiquitylating, possibly causing degradation of key effector proteins of the migration/invasion machinery.
      In support of its promoting role in metastasis (
      • Mahoney M.G.
      • Simpson A.
      • Jost M.
      • Noé M.
      • Kari C.
      • Pepe D.
      • Choi Y.W.
      • Uitto J.
      • Rodeck U.
      Metastasis-associated protein (MTA)1 enhances migration, invasion, and anchorage-independent survival of immortalized human keratinocytes.
      ,
      • Nicolson G.L.
      • Nawa A.
      • Toh Y.
      • Taniguchi S.
      • Nishimori K.
      • Moustafa A.
      Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation, and nuclear regulation.
      ,
      • Hofer M.D.
      • Menke A.
      • Genze F.
      • Gierschik P.
      • Giehl K.
      Expression of MTA1 promotes motility and invasiveness of PANC-1 pancreatic carcinoma cells.
      ), we demonstrated that MTA1 expression enhances cell migration and invasion ability in MCF-7 cells (Fig. 7). More interestingly, we demonstrated that siRNA-mediated knockdown of endogenous RNF144A accelerates the motility and invasion of MTA1-overexpressing cells, suggesting that the effect of MTA1 on cell migratory and invasive functions is dependent on RNF144A expression. Thus, MTA1 facilitates the acquisition of an invasive and metastatic phenotype of cancer cells by, at least in part, compromising the suppressive function of RNF144A in tumor migration and invasion through transcriptional repression of RNF144A expression, and the dysregulated MTA1-RNF144A pathway augments the capacity of cancer cells for metastatic dissemination.
      In summary, we demonstrate that RNF144A is a direct target of transcriptional repression by MTA1 and is a novel potential inhibitor of cell migration and invasion. MTA1 overexpression in highly metastatic tumor cells inhibits RNF144A expression and function, facilitating the acquisition of a highly invasive and metastatic phenotype of cancer cells. In addition, as RNF144A protein contains a putative RING finger domain and MTA1 is an ubiquitinated protein (
      • Li D.Q.
      • Ohshiro K.
      • Reddy S.D.
      • Pakala S.B.
      • Lee M.H.
      • Zhang Y.
      • Rayala S.K.
      • Kumar R.
      E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1.
      ), it will be interesting to determine whether MTA1 would be targeted by RNF144A as a potential E3 ubiquitin-protein ligase for the ubiquitin-dependent degradation. Thus, MTA1 and RNF144A may form a double vicious circle, contributing to tumor aggressiveness and progression. Collectively, the results presented here provide novel mechanistic insights into regulation of tumor progression by MTA1 and highlight a previously unrecognized role of RNF144A in MTA1-driven cancer cell migration and invasiveness. These findings open the possibility that development of specific modifiers of the MTA1-RNF144A pathway may lead to novel therapeutic approaches for targeting the metastatic process in the future.

      Acknowledgments

      We thank all the members of the Kumar laboratory for technical assistance and fruitful discussion and are grateful to Dr. Lei Wang (Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX) for microarray data mining.

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