Increased copy‐number and not DNA hypomethylation causes overexpression of the candidate proto‐oncogene CYP24A1 in colorectal cancer. Issue 6 (5th April 2013)

• Record Type: Journal Article
• Authors: Höbaus, Julia; Hummel, Doris M.; Thiem, Ursula; Fetahu, Irfete S.; Aggarwal, Abhishek; Müllauer, Leonhard; Heller, Gerwin; Egger, Gerda; Mesteri, Ildiko; Baumgartner‐Parzer, Sabina; Kallay, Enikö
• Is Part Of: International journal of cancer. Volume 133:Issue 6(2013:Sep. 15)
• Page Start: 1380
• Page End: 1388
• Publication Date: 2013-04-05
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28143
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>In colorectal cancer (CRC) the vitamin D catabolizing enzyme 1, 25‐dihydroxyvitamin D 24‐hydroxylase (CYP24A1) is overexpressed with a potentially significant, positive impact on the catabolism of 1, 25‐dihydroxyvitamin D<sub>3</sub> (1, 25‐D<sub>3</sub>). However, the underlying mechanism of CYP24A1 overexpression is poorly understood. In the present study, we investigated possible causes including hypomethylation of the CYP24A1 promoter, amplification of the <italic>CYP24A1</italic> gene locus (20q13.2), and altered expression of <italic>CYP24A1</italic>‐specific transcription factors. We quantified CYP24A1 gene copy‐number, performed bisulfite sequencing of the <italic>CYP24A1</italic> promoter to assess DNA methylation, and measured mRNA expression of CYP24A1, 25‐hydroxyvitamin D 1α‐hydroxylase (CYP27B1), vitamin D receptor (VDR) and retinoid X receptor (RXR). We found that 77 (60%) out of 127 colorectal tumors showed increased CYP24A1 gene copy‐number and that more than 6 copies of <italic>CYP24A1</italic> correlated positively with CYP24A1 mRNA expression suggestive of a causal relationship. No differences in <italic>CYP24A1</italic> promoter methylation were found between tumor tissue and adjacent mucosa from the same patient or between tissues with high or low mRNA expression, thus excluding DNA hypomethylation as a possible cause of CYP24A1 overexpression in CRC. Furthermore, mRNA expression of several factors involved in replication licensing positively correlated with CYP24A1 mRNA expression, raising the possibility that CYP24A1 overexpression might favor increased proliferation in tumors by suppressing local 1, 25‐D<sub>3</sub> levels. We conclude that high copy‐number gain is a key determinant of CYP24A1 overexpression in CRC. Other postulated causes of CYP24A1 overexpression including promoter hypomethylation and enhanced VDR and/or RXR expression do not appear to be involved.</p> </abstract>