HIC1 Modulates Prostate Cancer Progression by Epigenetic Modification

Abstract

Purpose: 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.Experimental Design: 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.

Bmi-1 expression modulates non-small cell lung cancer progression

“…30 In this study, we used agilent-014850 whole human genome microarrays 4 £ 44K G4112F.This Chip targets > 20,000 genes with >40000 probes originated from a broad survey of well known sources such as Ensembl, Goldenpath, RefSeq, Unigene and others. Total RNA (>300 ng) were extracted from A549/control shRNA and A549/Bmi-1shRNA cells.…”

“…Subcutaneous tumors were established as described previously. 30 Briefly, 5-to 6-week-old BALB/c nude mice (Slaccas Laboratory Animal, Shanghai, China) were subcutaneously injected with cells (2 £ 10 6 /mouse) in PBS solution, and tumor sizes were measured every 5 day in order to calculate tumor volumes. All mice were sacrificed 5 weeks after injection.…”

“…The modified transplantation through tail vein injection is referred to in the report of Zheng et al 30 Briefly, Tail vein injections were performed to determine whether that Bmi-1 played a role in metastasis. 5-to 6-week-old BALB/c nude mice (Slaccas Laboratory Animal, Shanghai, China) were injected into tail vein with cells (1 £ 10 6 /mouse) in PBS solution.…”

Germ-line MTHFR C677T, FV H1299R and PAI-1 5G/4G Variations in Breast Carcinoma

“…Epigenetic alterations in cancer-related genes are recognized to play an important role in BC carcinogenesis. Epidemiological studies have consistently supported that cancer is related not only to mutations in functional genes but also related to the aberrant epigenetic modifications of various genes (Chang and Sharan, 2012;Jeong et al, 2013;Martin, 2013;Zheng et al, 2013). Altered DNA methylation profiles play crucial role in miRNAs process and this are important regulators of gene expression that are frequently deregulated in cancer.…”

Expression of the tumor suppressor gene hypermethylated in cancer 1 in laryngeal carcinoma

“…the level of the mRNA transcript. Zheng et al (32) analyzed the hypermethylation of HIC1 and concluded that the hypermethylation did not consistently correlate with the HIC1 expression level in breast and non-small-cell lung cancer.…”