title: HDAC 1 and 6 modulate cell invasion and migration in clear cell renal cell carcinoma.
abstract: Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown.
  
  
  
  Four isogenic cell lines C2/C2VHL and 786-O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2α knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student's T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival.
  
  
  
  Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2α is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ERα) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated α-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset.
  
  
  
  Taking together, these results suggest that HDAC1 and HDAC6 may play a role in ccRCC biology and could represent rational therapeutic targets.
authors: Department of Cancer Pathology and Prevention, Roswell Park Cancer Institute, Buffalo, NY, USA.|Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Swathi
authors: S
authors: Ramakrishnan
authors: Department of Cancer Pathology and Prevention, Roswell Park Cancer Institute, Buffalo, NY, USA.|Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: ShengYu
authors: S
authors: Ku
authors: Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy.
authors: Eric
authors: E
authors: Ciamporcero
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Kiersten Marie
authors: KM
authors: Miles
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Kris
authors: K
authors: Attwood
authors: Genitourinary Program, Indiana University- Simon Cancer Center, Indianapolis, IN, USA.
authors: Sreenivasulu
authors: S
authors: Chintala
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Li
authors: L
authors: Shen
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Leigh
authors: L
authors: Ellis
authors: Center for Integrative Medicine and Innovative Science-Universidad Andres Bello, Santiago, Chile.
authors: Paula
authors: P
authors: Sotomayor
authors: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Wendy
authors: W
authors: Swetzig
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Ray
authors: R
authors: Huang
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Dylan
authors: D
authors: Conroy
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.|Genitourinary Program, Indiana University- Simon Cancer Center, Indianapolis, IN, USA.
authors: Ashley
authors: A
authors: Orillion
authors: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Gokul
authors: G
authors: Das
authors: Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA. rpili@iupui.edu.|Genitourinary Program, Indiana University- Simon Cancer Center, Indianapolis, IN, USA. rpili@iupui.edu.
authors: Roberto
authors: R
authors: Pili
mesh_terms: D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D047369:Chromatin Immunoprecipitation; D018572:Disease-Free Survival; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D046888:Tissue Array Analysis
chemical_list: C110550:HDAC1 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases