Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation

Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Cancer (Impact Factor: 4.89). 04/2008; 112(7):1489-502. DOI: 10.1002/cncr.23323
Source: PubMed


Imprinted tumor suppressor genes may be particularly important in the pathogenesis of ovarian cancer. Two imprinted genes, paternally expressed 3 (PEG3) and aplasia Ras homologue member I (ARHI), are the most frequently down-regulated in ovarian cancers on gene expression arrays.
PEG3 and ARHI expression levels were evaluated with real-time reverse-transcriptase polymerase chain reaction (PCR) analysis. Promoter methylation was measured by pyrosequencing, and loss of heterozygosity (LOH) was detected by PCR-LOH assays.
PEG3 was down-regulated in 75% and ARHI was down-regulated in 88% of 40 ovarian cancers. ARHI CpG islands I and II were hypermethylated in 13 of 42 ovarian cancers (31%) and in 5 of 42 ovarian cancers (12%), respectively, and hypermethylation was associated with reduced ARHI expression in all 18 samples of ovarian cancer with CpG island hypermethylation. PEG3 was hypermethylated in 11 of 42 ovarian cancers (26%), and PEG3 expression was down-regulated in 10 of those 11 cancers. LOH was detected in 8 of 35 informative cases for ARHI (23%) and in 5 of 25 informative cases for PEG3 (20%). PEG3 and ARHI expression was highly correlated in human ovarian cancers (correlation coefficient [R]=0.69; P< .0001). PEG3 and ARHI also were methylated concordantly in ovarian cancers (R=0.36; P= .019). Re-expression of PEG3, similar to that of ARHI, markedly inhibited ovarian cancer growth. ARHI and PEG3 expression could be restored by treatment with 5-aza-2'-deoxycytidine and trichostatin A, consistent with the importance of promoter methylation and histone acetylation in regulating expression of both genes.
Loss of expression of the growth-inhibitory imprinted genes ARHI and PEG3 through promoter methylation, LOH, and other mechanisms may stimulate clonogenic growth and contribute to the pathogenesis of a majority of ovarian cancers.


Available from: Zhen Lu, Sep 26, 2014
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    • "ARHI could also suppress ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways [30]. Like other tumor suppressors, ARHI expression could be regulated by deletion of an allele and promoter methylation [31], transcriptional factors and HDAC-containing complexes [32,33]. E2F1 and E2F4 are reported to negatively regulate ARHI expression by forming complex with HDAC. "
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    • "In humans, the PEG3-DMR is known to be an epigenetically susceptible region: many patients of ovarian, breast and glioma cancers tend to lose the expression of PEG3 mainly due to DNA hypermethylation on the PEG3-DMR [14]–[19]. Interestingly, reintroducing PEG3 into primary cell lines derived from these cancer patients inhibited cell growth, demonstrating tumor suppressor activity [17],[19]. Thus, PEG3 has been often regarded as a potential tumor suppressor in humans. "
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