title: LIM-Only Protein 4 (LMO4) and LIM Domain Binding Protein 1 (LDB1) Promote Growth and Metastasis of Human Head and Neck Cancer (LMO4 and LDB1 in Head and Neck Cancer).
abstract: Squamous cell carcinoma of the head and neck (HNSCC) accounts for more than 300,000 deaths worldwide per year as a consequence of tumor cell invasion of adjacent structures or metastasis. LIM-only protein 4 (LMO4) and LIM-domain binding protein 1 (LDB1), two directly interacting transcriptional adaptors that have important roles in normal epithelial cell differentiation, have been associated with increased metastasis, decreased differentiation, and shortened survival in carcinoma of the breast. Here, we implicate two LDB1-binding proteins, single-stranded binding protein 2 (SSBP2) and 3 (SSBP3), in controlling LMO4 and LDB1 protein abundance in HNSCC and in regulating specific tumor cell functions in this disease. First, we found that the relative abundance of LMO4, LDB1, and the two SSBPs correlated very significantly in a panel of human HNSCC cell lines. Second, expression of these proteins in tumor primaries and lymph nodes involved by metastasis were concordant in 3 of 3 sets of tissue. Third, using a Matrigel invasion and organotypic reconstruct assay, CRISPR/Cas9-mediated deletion of LDB1 in the VU-SCC-1729 cell line, which is highly invasive of basement membrane and cellular monolayers, reduced tumor cell invasiveness and migration, as well as proliferation on tissue culture plastic. Finally, inactivation of the LDB1 gene in these cells decreased growth and vascularization of xenografted human tumor cells in vivo. These data show that LMO4, LDB1, and SSBP2 and/or SSBP3 regulate metastasis, proliferation, and angiogenesis in HNSCC and provide the first evidence that SSBPs control LMO4 and LDB1 protein abundance in a cancer context.
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors: Elizabeth A
authors: EA
authors: Simonik
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors: Ying
authors: Y
authors: Cai
authors: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors: Katherine N
authors: KN
authors: Kimmelshue
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors: Dana M
authors: DM
authors: Brantley-Sieders
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors: Holli A
authors: HA
authors: Loomans
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States of America.|Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, United States of America.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors: Claudia D
authors: CD
authors: Andl
authors: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors: Grant M
authors: GM
authors: Westlake
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors: Victoria M
authors: VM
authors: Youngblood
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States of America.|Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America.|Department of Cell & Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, United States of America.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, United States of America.|VA Tennessee Valley Healthcare System, Nashville, TN, United States of America.
authors: Jin
authors: J
authors: Chen
authors: Department of Otolaryngology and Barry Baker Laboratory for Head and Neck Oncology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors: Wendell G
authors: WG
authors: Yarbrough
authors: Department of Otolaryngology and Barry Baker Laboratory for Head and Neck Oncology, Vanderbilt University School of Medicine, Nashville, TN, United States of America.
authors: Brandee T
authors: BT
authors: Brown
authors: Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States of America.
authors: Lalitha
authors: L
authors: Nagarajan
authors: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States of America.|Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America.|Department of Cell & Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, United States of America.|Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, United States of America.|VA Tennessee Valley Healthcare System, Nashville, TN, United States of America.
authors: Stephen J
authors: SJ
authors: Brandt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism*; D051379:Mice; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C486312:LDB1 protein, human; D060588:LIM Domain Proteins; C114905:LMO4 protein, human; C477058:SSBP2 protein, human; C504094:SSBP3 protein, human; D014157:Transcription Factors