Retinoblastoma-binding protein 2 (RBP2) is frequently expressed in neuroendocrine tumors and promotes the neoplastic phenotype.

E C Maggi,J Trillo-Tinoco,J Vijayaraghavan,J S Crabtree,L Del Valle,A P Struckhoff

doi:10.1038/oncsis.2016.58

Abstract

Neuroendocrine tumors (NETs), which can have survival rates as low as 4%, currently have limited therapeutic interventions available highlighting the dire need for the identification of novel biological targets for use as new potential drug targets. One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types. We measured RBP2 mRNA and protein levels in enteropancreatic NETs by measuring RBP2 in matched human normal and NET tissue samples. Further, proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines βlox5, H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis. Our data indicate a strong correlation between RBP2 mRNA and protein expression in NET specimens. RBP2 was overexpressed relative to tissue-matched normal controls in 80% of the human tumors measured. In vitro studies showed RBP2 overexpression significantly increased proliferation, migration, invasion and colony formation, whereas knockdown significantly decreases the same parameters in a demethylase-independent manner. The cell cycle inhibitors p21 and p57 decreased with RBP2 overexpression and increased upon its depletion, suggesting a regulatory role for RBP2 in cellular proliferation. Taken together, our results support the hypothesis that the aberrant overexpression of RBP2 is a frequent contributing factor to tumor formation and metastasis in enteropancreatic NETs.

Highlights

Neuroendocrine tumors (NETs) arise from neuroendocrine tissues in the lung, pancreas, gut and bowel, and pose a significant threat because of their high metastatic potential
One such potential target is retinoblastoma-binding protein 2 (RBP2), an H3K4 demethylase whose overexpression has been linked to cancer formation and metastasis in non-endocrine tumor types
RBP2 expression is elevated in NETs RBP2 was significantly elevated at the RNA level in 20 out of 25 human tumor samples compared with matched normal tissue (Figure 1a), with an average upregulation greater than threefold (Figure 1b)

Summary

Introduction

Neuroendocrine tumors (NETs) arise from neuroendocrine tissues in the lung, pancreas, gut and bowel, and pose a significant threat because of their high metastatic potential. Proliferation, migration, invasion and colony formation assays were performed in the physiologically relevant NET cell lines βlox[5], H727 and QGP-1 to understand the role of RBP2 and its demethylase activity on end points of tumorigenesis.

Results

Conclusion