Regulation of vitamin D receptor function in MEN1-related parathyroid adenomas.
Multiple endocrine neoplasia type 1 (MEN1) is a heriditary syndrome characterised by the occurrence of parathyroid, gastroenteropancreatic and pituitary tumours. The MEN1 gene product, menin, co-activates gene transcription by recruiting histone methyltransferases for lysine 4 of histone H3 (H3K4). We investigated whether in MEN1 tumours global changes in H3K4 trimethylation (H3K4me3) occur or whether alterations in gene expression can be observed. By immunohistochemistry we found that global levels of H3K4me3 are not affected in MEN1-related parathyroid adenomas. Menin can interact directly with the vitamin D receptor (VDR) and enhance the transcriptional activity of VDR. Messenger RNA levels of VDR target genes CYP24 and KLK6 were significantly lower in MEN1 parathyroid adenomas compared to normal tissue. Thus, aberrant gene expression in MEN1 tumours is not caused by lower global H3K4me3, but rather by specific effects on genes that are regulated by menin-interacting proteins, such as VDR.
Dreijerink
Koen M A
KM
Department of Physiological Chemistry, University Medical Center Utrecht, Utrecht, The Netherlands.
Varier
Radhika A
RA
van Nuland
Rick
R
Broekhuizen
Roel
R
Valk
Gerlof D
GD
van der Wal
Jacqueline E
JE
Lips
Cornelis J M
CJ
Kummer
J Alain
JA
Timmers
H Th Marc
HT
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D018761:Multiple Endocrine Neoplasia Type 1 / Q000378:metabolism / Q000473:pathology; D010282:Parathyroid Neoplasms / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D006657:Histones; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D018167:Receptors, Calcitriol; D008239:Lysine