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Significant Biological Role of Sp1 Transactivation in Multiple Myeloma

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Significant Biological Role of Sp1 Transactivation in Multiple Myeloma Published OnlineFirst August 19, 2011; DOI: 10.1158/1078-0432.CCR-11-1036 Clinical Cancer Cancer Therapy: Preclinical Research Significant Biological Role of Sp1 Transactivation in Multiple Myeloma Mariateresa Fulciniti1,2, Samir Amin1, Puru Nanjappa1, Scott Rodig1, Rao Prabhala2, Cheng Li1, Stephane Minvielle3, Yu-tzu Tai1, Pierfrancesco Tassone4, Herve Avet-Loiseau3, Teru Hideshima1, Kenneth C. Anderson1, and Nikhil C. Munshi1,2 Abstract Purpose: The transcription factor specificity protein 1 (Sp1) controls number of cellular processes by regulating the expression of critical cell cycle, differentiation, and apoptosis-related genes containing proximal GC/GT-rich promoter elements. We here provide experimental and clinical evidence that Sp1 plays an important regulatory role in multiple myeloma (MM) cell growth and survival. Experimental Design: We have investigated the functional Sp1 activity in MM cells using a plasmid with Firefly luciferase reporter gene driven by Sp1-responsive promoter. We have also used both siRNA- and short hairpin RNA–mediated Sp1 knockdown to investigate the growth and survival effects of Sp1 on MM cells and further investigated the anti-MM activity of terameprocol (TMP), a small molecule that specifically competes with Sp1-DNA binding in vitro and in vivo. Results: We have confirmed high Sp1 activity in MM cells that is further induced by adhesion to bone marrow stromal cells (BMSC). Sp1 knockdown decreases MM cell proliferation and induces apoptosis. Sp1-DNA binding inhibition by TMP inhibits MM cell growth both in vitro and in vivo, inducing caspase- 9–dependent apoptosis and overcoming the protective effects of BMSCs. Conclusions: Our results show Sp1 as an important transcription factor in myeloma that can be therapeutically targeted for clinical application by TMP. Clin Cancer Res; 17(20); 6500–9. Ó2011 AACR. Introduction chromatin-modifying factors such as p300 (3) and histone deacetylases (HDAC; ref. 4). Specificity protein 1 (Sp1) and other Sp and Kruppel-like Although Sp1 has been considered as a ubiquitous factor proteins are members of a family of transcription transcription factor, increasing evidence suggests that it factors that bind GC/GT-rich promoter elements through 3 plays a major role in regulating expression of cell differ- C2H2-type zinc fingers that are present at their C-terminal entiation, cell cycle, and apoptosis-related genes affecting domains (1). cellular growth (5). Sp1 levels and/or activity are increased Sp1 regulates gene expression both by direct interaction in multiple cancers including breast (6), colon (7), gastric with promoter elements and via protein–protein interac- (8), pancreatic (9–12), and thyroid cancer (13) as com- tions or interplay with other transcription factors, such as pared with normal tissues. Elevated Sp1 expression is Ets-1, c-myc, c-Jun, Stat1, and Egr-1, and/or components of inversely correlated with the survival of patients with gastric the basal transcriptional machinery (2). Sp1 has also been cancer (14) and identifies advanced stage tumors and linked to chromatin remodeling through interactions with predicts a poor clinical outcome in primary pancreatic adenocarcinoma (12). On the other hand, interference of Sp1 activity has been shown to suppress tumor cell growth (15, 16) as well as tumor formation in athymic Authors' Affiliations: 1Jerome Lipper Multiple Myeloma Center, Dana- mice (6, 17), suggesting that Sp1 plays a central regulatory Farber Cancer Institute; 2VA Boston Healthcare System, Harvard Medical role in controlling the number of pathways of tumor School, Boston, Massachusetts; 3Centre Hospitalier Universitaire de development and progression and thus may be an attrac- Nantes, IRCNA, Laboratoire d’Hematologie, Nantes, France; and 4University of "Magna Græcia," Catanzaro, Italy tive therapeutic target. Sp1 could contribute to transformation via regulation of Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). the expression of Sp1-responsive genes including those c-jun Raf cyclins E2F1 TGF-b Corresponding Author: Nikhil C. Munshi, Dana-Farber Cancer Institute, supporting cell growth ( , , , , , 450 Brookline Ave, Boston, MA 02115. Phone: 617-632-4166; Fax: 617- IEX-1, and TCL1; refs. 18, 19) and apoptosis (Bcl-2, survivin; 632-5829; E-mail: [email protected] refs. 5, 20). Sp1 also regulates genes involved in angiogen- doi: 10.1158/1078-0432.CCR-11-1036 esis and metastasis, including VEGF, uPA (21), PSA, and Ó2011 American Association for Cancer Research. MT1-MMP (22). Enhanced Sp1 activity is related to both 6500 Clin Cancer Res; 17(20) October 15, 2011 Downloaded from clincancerres.aacrjournals.org on October 5, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst August 19, 2011; DOI: 10.1158/1078-0432.CCR-11-1036 Sp1 Activity Inhibition as MM Therapeutic Target Translational Relevance Reagents Terameprocol (TMP), kindly provided by Erimos Phar- The transcription factor specificity protein 1 (Sp1) maceuticals, was synthesized and dissolved in 30 hydro- affects growth and metastatic potential of tumor cells. xypropyl CPE B-cyclodextrin and 25 polyethylene glycol In MM, key genes such as NF-kB p65, IGF-IR, VEGF, and 300 as previously described (30). IL-6 contain proximal GC-rich promoter sequences, and their interactions with Sp proteins are critical for Cell proliferation assay 3 their expression. Here, we show that Sp1 plays an MM cell proliferation was measured by [ H]thymidine important role in myeloma cell growth and survival. (Perkin-Elmer) incorporation assay as previously described Importantly, Sp1-specific inhibitor can induce tumor (29). apoptosis in murine models of MM. Thus, inhibition of Sp1 may be an attractive therapeutic modality in Bromodeoxyuridine staining MM, alone or in combination with other agents. The proportion of myeloma cells in S-phase was deter- mined by incorporation of bromodeoxyuridine (BrdUrd). A total of 1 Â 106 MM cells were exposed to 10 mg/mL of BrdUrd for 30 minutes. The cells were then harvested and stained with FITC anti-BrdUrd antibody and 7-aminoacti- increased Sp1 gene expression and its posttranslational nomycin D (7-AAD) using a BrdU Flow kit (BD Bioscience modification; for example, Sp1 phosphorylation regulates Pharmingen) according to the manufacturer’s directions. target genes in both positive and negative directions Cells were analyzed by flow cytometric analysis with a (23, 24). Becton-Dickinson FACScan flow cytometer. Although Sp1 has been described to modulate autocrine interleukin (IL)-6 secretion by multiple myeloma (MM) Apoptosis assay cells affecting its growth (25), its role in MM pathobiology Apoptosis was evaluated by flow cytometric analysis remains unexplored. The promoter of several genes such as following Annexin-V and propidium iodide (PI) staining. NF-kB p65, IGF-IR, VEGF, hTERT, and IL-6 that regulate MM cell growth, cell-cycle progression, survival, and apo- Sp1 binding activity ptosis contains proximal GC-rich promoter sequences that The Sp1 binding activity was analyzed using the Tran- interact with Sp1 protein for their optimal expression (25– scription Factor ELISA Kit, a DNA-binding ELISA-based 28). In addition, the same kinase pathways that have been assay (Panomics). Sp1 transcription factor binding to its shown to increase Sp1 phosphorylation and the transacti- consensus sequence on the plate-bound oligonucleotide vation of target genes (21, 22) are also known to mediate was studied from nuclear extracts, following the man- proliferation, survival, drug resistance, and migration ufacturer’s procedure. Briefly, nuclear proteins were (ERK, Jak/STAT, PI3K/Akt, and PKC signaling cascades, extracted with a Nuclear Extraction kit (Panomics) and respectively) in MM. quantified using the Bio-Rad Protein Assay Kit (Bio-Rad). A Here, we report significant role of Sp1 in myeloma cell total of 15 mg of nuclear protein from each treatment was growth and survival. Our results suggest that Sp1 activity analyzed. Sp1 antibody was used as the primary antibody, can be therapeutically targeted for clinical application in and anti-rabbit IgG horseradish peroxidase was used as the MM. secondary antibody. The absorbance was measured at a wavelength of 450 nm on a spectrophotometer. Materials and Methods Promoter activity assay Cells The Sp1 promoter reporter constructs were purchased Bone marrow mononuclear cells and primary MM cells from Sabiosciences. To examine transcriptional regulation from bone marrow aspirates from MM patients following of the Sp1 promoter by TMP, MM cells were transiently informed consent and Dana-Farber Cancer Institute Insti- transfected with 1 mg of Sp1 reporter plasmid or empty tutional Review Board (IRB) approval were isolated by vector control by electroporation using AMAXA technology Ficoll–Hypaque density gradient sedimentation. MM according to the manufacturer’s instructions. Luciferase patient cells were separated from bone marrow samples assays were done with a Luminoskan Ascent 2.4 lumin- by antibody-mediated positive selection using anti-CD138 ometer and the Dual-Luciferase Reporter Assay System magnetic-activated cell separation microbeads (Miltenyi (Promega). Firefly luciferase values were normalized to Biotech). Bone marrow stromal cells (BMSC) were estab- Renilla luciferase activity and were either expressed as lished as previously described (29). MM cell lines were relative luciferase units (RLU) or as mean
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