Research Papers:

Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells

Marije J. Veenstra, Peter M. van Koetsveld, Fadime Dogan, William E. Farrell, Richard A. Feelders, Steven W.J. Lamberts, Wouter W. de Herder, Giovanni Vitale and Leo J. Hofland _

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Oncotarget. 2018; 9:14791-14802. https://doi.org/10.18632/oncotarget.9462

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Marije J. Veenstra1, Peter M. van Koetsveld1, Fadime Dogan1, William E. Farrell2, Richard A. Feelders1, Steven W.J. Lamberts1, Wouter W. de Herder1, Giovanni Vitale3,4, Leo J. Hofland1

1Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, The Netherlands

2Department Human Disease and Genomics Group, Institute of Science and Technology in Medicine, School of Medicine, Keele University, Keele, United Kingdom

3Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy

4Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy

Correspondence to:

Leo J. Hofland, email: [email protected]

Keywords: pancreatic neuroendocrine tumor; somatostatin receptor type 2; epigenetics; BON-1; QGP-1

Received: November 19, 2015     Accepted: April 24, 2016     Epub: May 19, 2016     Published: March 13, 2018


Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2’-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs.

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