Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer

Abstract

Epigenetic deregulation is of importance in tumorigenesis. In particular CpG islands (CGI), are frequently hypermethylated. Here, genome-wide DNA-methylation profiles of 480,000 CpGs in lung cancer cells were generated. It was observed that intra- and intergenic CGI exhibited higher methylation compared to normal cells. The functional annotation of hypermethylated CGI revealed that the hypermethylation was associated with homeobox domain genes and targets marked by repressive histone modifications. The strongest methylation variation was observed in transitional areas of CGI, termed shores. 5′-shores of promoter-associated CGI in lung cancer cell lines were higher methylated than 3′-shores. Within two tandem-oriented genes, a significant hypermethylation of the downstream-located CGI promoters was revealed. Hypermethylation correlates with the length of the intergenic region between such tandem genes. As the RASSF1A tumor suppressor gene represents such a downstream tandem gene, its silencing was analyzed using an inducible system. It was determined that the induction of an upstream gene led to a repression of RASSF1A through a process involving histone deacetylases and CPSF1. A tumor-specific increase in expression of histone deacetylases and CPSF1 was detected in lung cancer. Our results suggest that the downstream gene could be susceptible to epigenetic silencing when organized in a tandem orientation.

Impact of Natural Compounds on DNA Methylation Levels of the Tumor Suppressor Gene RASSF1A in Cancer

“…This indicates that the RASSF1A promoter is susceptible to its epigenetic silencing. Recently, we revealed that for tandem-oriented genes, the downstream gene is significantly higher methylated when the transcriptional end site of the upstream gene is in proximity (<1 kb distance) with the transcriptional start site [ 51 ]. The RASSF1A promoter is located only 200 bp downstream of the last exon of the ZMYND10 gene ( Figure 1 ).…”

“…ZYMND10 encodes a protein containing a MYND-type zinc finger domain, that likely functions in assembly of the dynein motor [ 52 ]. In lung cancer, we observed a hypomethylation of the ZYMND10 promoter and increased expression of its transcript [ 51 ]. This data suggest that through its genomic organization RASSF1A is prone to epigenetic silencing.…”

“…This data suggest that through its genomic organization RASSF1A is prone to epigenetic silencing. Additionally, in cancer we and others observed that aberrant expression of DNMT1, DNMT3A, DNMT3B and histone deacetylases (HDAC) is involved in the inactivation process of RASSF1A [ 51 , 53 , 54 , 55 , 56 ].…”

HOXA5 inhibits the proliferation and induces the apoptosis of cervical cancer cells via regulation of protein kinase B and p27

“…The expression and dysfunction of homeobox (HOX) genes play an important role in the development of various malignant tumors, such as lung cancer, breast cancer, colon cancer, prostate cancer and leukemia (6)(7)(8)(9). HOXA5 is a member of HOX gene family and is a transcriptional regulator that regulates cell growth, differentiation and apoptosis (10,11).…”

Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing

“…Burge et al showed that proliferating cells exhibited genome-wide truncation of mRNA structure (especially 3'UTRs) [5]. Kiehl et al [24] reported that a significant increase in CPSF1 expression was detected in lung cancer samples in comparison with normal lung, and it suppressed the RASSF1A tumor suppressor gene, which is epigenetically inactivated in a wide range of cancer types [25]. Van Etten et al [26] reported that CPSF1 regulates Androgen receptor (AR) splice variant expression in prostate cancer.…”