TRIM13 (RFP2) downregulation decreases tumour cell growth in multiple myeloma through inhibition of NF Kappa B pathway and proteasome activity

• Published in: British journal of haematology 2013-07, Vol.162 (2), p.210-220
• Main Authors: Gatt, Moshe E., Takada, Kohichi, Mani, Mala, Lerner, Mikael, Pick, Marjorie, Hideshima, Teru, Carrasco, Daniel E., Protopopov, Alexei, Ivanova, Elena, Sangfelt, Olle, Grandér, Dan, Barlogie, Bart, Shaughnessy, John D., Anderson, Kenneth C., Carrasco, Daniel R.
• Format: Article
• Language: English
• Subjects: 13q; Apoptosis - genetics; Biological and medical sciences; Cell Cycle - genetics; Cell Division - genetics; Cell Line, Tumor; Cell Survival - genetics; Chromosome Deletion; Chromosomes, Human, Pair 13; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Gene Expression Profiling; Gene Knockdown Techniques; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicin och hälsovetenskap; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; myeloma; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; proliferation; proteasome; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; TRIM13 (RFP2); Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.12365

Summary Multiple myeloma (MM) is an incurable neoplasm caused by proliferation of malignant plasma cells in the bone marrow (BM). MM is characterized frequently by a complete or partial deletion of chromosome 13q14, seen in more than 50% of patients at diagnosis. Within this deleted region the tripartite motif containing 13 (TRIM13, also termed RFP2) gene product has been proposed to be a tumour suppressor gene (TSG). Here, we show that low expression levels of TRIM13 in MM are associated with chromosome 13q deletion and poor clinical outcome. We present a functional analysis of TRIM13 using a loss‐of‐function approach, and demonstrate that TRIM13 downregulation decreases tumour cell survival as well as cell cycle progression and proliferation of MM cells. In addition, we provide evidence for the involvement of TRIM13 downregulation in inhibiting the NF kappa B pathway and the activity of the 20S proteasome. Although this data does not support a role of TRIM13 as a TSG, it substantiates important roles of TRIM13 in MM tumour survival and proliferation, underscoring its potential role as a novel target for therapeutic intervention.