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Identification of an Upstream Promoter of the Human Somatostatin Receptor, hSSTR2, Which Is Controlled by Epigenetic Modifications

Institut National de la Santé et de la Recherche Médicale Unité 858-I2MR (J.T., N.H., H.L., A.S., C.S., P.C., L.B.), Institut de Médecine Moléculaire de Rangueil, Département Cancers Epithéliaux, Angiogénèse, et Signalisation, 31432 Toulouse Cedex 4, France; Institut Fédératif de Recherche 31 (F.L., J.-J.M.), Toulouse Rangueil, Plateformes de Génomique et Biologie Moléculaire/Protéomique et Intéractions Moléculaires, and Service de Gastroentérologie (L.B.), Centre Hospitalier Universitaire Rangueil, 31059 Toulouse, France

Address all correspondence and requests for reprints to: Louis Buscail, M.D., Ph.D., Institut National de Santé et Recherche Médicale Unité 858, I2MR Institut de Médecine Moléculaire de Rangueil, Département Cancers Epithéliaux, Angiogénèse, et Signalisation 1, avenue Jean Poulhès, BP 84225, 31432 Toulouse Cedex 4, France. E-mail: louis.buscail{at}toulouse.inserm.fr.

Somatostatin is a neuropeptide that inhibits exocrine and endocrine secretions of several hormones and negatively regulates cell proliferation. These events are mediated through somatostatin engagement on one of five G protein-coupled receptors named SSTR1 to STTR5. Somatostatin binding to SSTR2 mediates predominantly antisecretory and antiproliferative effects; two important biological activities in the gastroenteropancreatic endocrine and exocrine system. Herein we demonstrate novel regulatory sequences for human (h) SSTR2 transcription. By genomic DNA sequence analysis, we reveal two CpG islands located 3.8 kb upstream from the transcription start site. We identify a novel transcription start site and a promoter region within one of these CpG islands. We demonstrate that two epigenetic modifications, DNA methylation and histone acetylation, regulate the activation of hSSTR2 upstream promoter. Furthermore, we show that the transcription from this upstream promoter region directly correlates to hSSTR2 mRNA expression in various human cell lines. A combined treatment of a demethylating agent, 5-aza-2-deoxycytidine and a histone deacetylase inhibitor, trichostatin A, leads to increased expression of hSSTR2 mRNA in cell lines in which the CpG island is methylated. The epigenetic regulation of this promoter region results in differential expression of hSSTR2 mRNA in human cell lines. This study reveals the existence of a novel upstream promoter for the hSSTR2 gene that is regulated by epigenetic modifications, suggesting for complex control of the hSSTR2 transcription.