Mutations and aberrant DNA methylation of the PROX1 gene in hematologic malignancies

Abstract

The homeobox gene PROX1 is related to the Drosophila prospero gene, which is expressed in the developing central nervous system and lens-secreting cone cells. We found that the PROX1 gene had missense and nonsense mutations in 4 of 29 hematologic cell lines analyzed. Decreased mRNA expression was also observed in half of these cell lines by RT-PCR. The restoration of PROX1 gene expression after treatment with the demethylating agent 5-aza-2'-deoxycytidine, as well as bisulfite sequencing analysis, indicated that gene silencing is caused by DNA hypermethylation at intron 1. Such hypermethylation was also seen in primary lymphomas (56.3%, 18/32) in a tumor-specific manner. These findings indicate that the profile of the PROX1 gene corresponds to that of a candidate tumor-suppressor gene.

The homeobox transcription factor Prox1 inhibits proliferation of hepatocellular carcinoma cells by inducing p53-dependent senescence-like phenotype

“…22,23,27,28 Recent studies showed that Prox1 may be involved in the progression or suppression of malignancies, such as HCC, cholangiocellular carcinoma, hematologic malignancies, breast cancer and pancreatic cancer. 18,19,24,25 How Prox1 acts as an oncogene or tumor suppressor gene in different cancer types is unclear. Petrova et al demonstrated that Prox1 induced colon cancer progression by promoting the transition from benign to highly dysplastic phenotype indicating a tumor-promoting role.…”

“…7 Recent studies demonstrate that p53 re-activation, c-Myc inhibition or treatment of cyclin-dependent kinase inhibitors (CDKIs) malignancies, pancreatic cancer and liver cancer indicating a tumor suppressor role of this transcription factor. [17][18][19][20] These studies suggest that Prox1 may function as an oncogene or a tumor suppressor gene in a cancer type-specific manner.…”

Expression of pituitary homeobox 1 gene in human gastric carcinogenesis and its clinicopathological significance

“…Another novel explanation for PITX1 tumorigenesis came from a study on the role of PITX1 in the transcription of the p53 tumor suppressor gene in human mammary carcinoma (MCF-7) cells, implying that p53 is a direct transcriptional target of PITX1 [24] . It has been long recognized that the inactivation of tumor suppressor genes results from mutation, loss of heterozygosity (LOH), aberrant methylation and haploinsufficiency [25,26] , among which aberrant promoter hyper methylation is well-known to par ticipate in homeobox gene silencing [27,28] ; however, PITX1 promoter hypermethylation has not been found in studies of lung cancer [19] . Therefore, we examined the PITX1 gene for the presence of mutations in order to explore the mechanism of inactivation of this candidate tumor suppressor gene.…”

Cancer Stem Cell Division: When the Rules of Asymmetry Are Broken

“…PROX1 alterations and reduced expression are seen in several forms of human neoplasia (Table 1), including hematologic malignancies, where DNA methylation of PROX1 is predominant (56.3%) and contributes to the neoplastic behavior [26]. In hepatocellular malignancies, PROX1 transcription is altered in a manner that promotes progression, while in breast cancer, epigenetic silencing has been described [27,28].…”