Abstract
Multiple myeloma SET (Suppressor of variegation, Enhancer of zeste, and Trithorax) domain (MMSET) is a histone lysine methyltransferase deregulated in a subgroup of multiple myelomas with the t(4;14)(p16;q32) translocation and poor prognosis. With the aim of understanding, if MMSET can be involved in other types of cancer we investigated the expression of MMSET protein in different types of human tumors. A monoclonal antibody against MMSET was developed and immunohistochemical staining of tissue microarrays (TMA) containing a large number of tumor samples (n = 3774) and corresponding normal tissues (n = 904) was carried out. Further validations of MMSET expression were carried out on independent, tumor-specific sets of TMAs for urinary bladder (n = 1293) and colon cancer (n = 1206) with corresponding clinicopathological data and long-term follow-up. MMSET protein was highly expressed in different tumor types compared to normal counterparts. Particular frequent and/or high MMSET expression was found in carcinomas of the gastrointestinal tract (stomach, colon, anal canal), small cell lung carcinoma, tumors of the urinary bladder, female genitals, and skin. In bladder cancer, MMSET expression correlated with tumor aggressiveness. In contrast, MMSET expression was associated with good prognostic factors in colon cancer and was more pronounced in early stages of colon carcinogenesis (dysplasias) than in adenocarcinomas. However, colon cancer patients with high MMSET levels showed a worse 5-year survival. Our data suggest that MMSET has a broader role in cancer than previously anticipated, and further analysis might qualify it as a prognostic marker and a target for the development of therapy against several types of cancer.
Highlights
MMSET/WolfHirschhorn syndrome candidate 1 (WHSC1)/NSD2 is a SET domain containing histone lysine methyltransferase that can di- and trimethylate histone H3 at lysine 36 (H3K36; refs. 1, 2)
U2OS cells were chosen for this test due to a relatively high expression of endogenous MMSET types I and II protein compared to many other cell lines tested but a lower expression than in t(4;14)þ myeloma cells lines (Supplementary Fig. S1A)
The 9A6 monoclonal antibody (mAb) was found to be effective in immunostainings when applied to the FFPE sections of U2OS cells (Fig. 1C and Supplementary Fig. S1B)
Summary
MMSET/WHSC1/NSD2 is a SET domain containing histone lysine methyltransferase that can di- and trimethylate histone H3 at lysine 36 (H3K36; refs. 1, 2). MMSET/WHSC1/NSD2 is a SET domain containing histone lysine methyltransferase that can di- and trimethylate histone H3 at lysine 36 Other specificities for MMSET have been reported [3,4,5]. The H3K36 methylation mark is present in transcriptionally active genes [6] presumably contributing to repression of inappropriate transcription inside transcribed genes [7, 8]. In addition to the SET domain, MMSET contains other. Authors' Affiliations: 1Biotech Research and Innovation Centre (BRIC), 2Centre for Epigenetics, and 3Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark; and 4Department of Pathology, University Medical Center Hamburg-Eppendorf, Germany. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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