title: HIC1 modulates prostate cancer progression by epigenetic modification.
abstract: OBJECTIVE
  Prostate cancer is the second leading cause of cancer deaths among men in Western counties, which has also occurred in Chinese male with markedly increasing incidence in recent years. Although the mechanism underlying its progression still remains unclear, epigenetic modifications are important ethological parameters. The purpose of this study is to determine the methylation status and function of hypermethylatioted in cancer 1 (HIC1) in prostate cancer progression.
  
  
  METHODS
  The methylation status of HIC1 promoter was assayed in cell lines, tissues, and plasma of patients with prostate cancer by using methylation-specific PCR and bisulfate sequencing PCR. The ability of HIC1 to regulate proliferation, migration, and invasion was assessed by MTT, scratch-healing assay, and reconstituted extracellular matrices in porous culture chambers. Tumorigenesis, metastases, and bone destruction were analyzed in mice bearing prostate cancer cells restoring HIC1 by using Xenogen IVIS with radiographic system and small-animal positron emission tomography computed tomographic images. Microarrays were searched for genes that had correlated expression with HIC1 mRNA. Reporter gene assays were used to determine whether HIC1 affected the expression of CXCR7, and chromatin immunoprecipitation was used to determine whether HIC1 bound to CXCR7 promoters. All P values were determined using 2-sided tests.
  
  
  RESULTS
  The methylation status of 11 CpG sites within HIC1 promoter was abundantly methylated in cell lines, tissues, and plasma of patients with prostate cancer compared with those of respective normal controls. Restoring HIC1 expression in prostate cancer cells markedly inhibited proliferation, migration, and invasion and induced the apoptosis in these cells. Moreover, mice bearing prostate cancer-restoring HIC1 cells had a marked effect on reducing tumor growth, multiple tissue metastases, and bone destruction. Notably, we also identified that the chemokine receptor CXCR7 is a direct downstream target gene of HIC1. Finally, we showed that CXCR7 promoter in prostate cancer cells is negatively regulated by HIC1, which may be responsible for prostate cancer progression.
  
  
  CONCLUSIONS
  Our data show for the first time that hypermethylation of HIC1 promoter results in loss of its repressive function, responsible for prostate cancer progression and invasion. These findings suggest that therapies targeting epigenetic events regulating HIC1 expression may provide a more effective strategy for prostate cancer treatment.
authors: Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, China.
authors: Jianghua
authors: J
authors: Zheng
authors: Jinglong
authors: J
authors: Wang
authors: Xueqing
authors: X
authors: Sun
authors: Mingang
authors: M
authors: Hao
authors: Tao
authors: T
authors: Ding
authors: Dan
authors: D
authors: Xiong
authors: Xiumin
authors: X
authors: Wang
authors: Yu
authors: Y
authors: Zhu
authors: Gang
authors: G
authors: Xiao
authors: Guangcun
authors: G
authors: Cheng
authors: Meizhong
authors: M
authors: Zhao
authors: Jian
authors: J
authors: Zhang
authors: Jianhua
authors: J
authors: Wang
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D054387:Receptors, CXCR / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C501896:ACKR3 protein, human; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D054387:Receptors, CXCR