The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome

Department of Research, Veterans Administration Boston Healthcare, West Roxbury, MA, USA.
Blood (Impact Factor: 10.45). 11/2009; 115(14):2827-34. DOI: 10.1182/blood-2009-03-211045
Source: PubMed


Multiple myeloma (MM) is a plasma cell neoplasm that proceeds through a premalignant state of monoclonal gammopathy of unknown significance; however, the molecular events responsible for myelomagenesis remain uncharacterized. To identify cellular pathways deregulated in MM, we addressed that sumoylation is homologous to ubiquitination and results in the attachment of the ubiquitin-like protein Sumo onto target proteins. Sumoylation was markedly enhanced in MM patient lysates compared with normal plasma cells and expression profiling indicated a relative induction of sumoylation pathway genes. The Sumo-conjugating enzyme Ube2I, the Sumo-ligase PIAS1, and the Sumo-inducer ARF were elevated in MM patient samples and cell lines. Survival correlated with expression because 80% of patients with low UBE2I and PIAS1 were living 6 years after transplantation, whereas only 45% of patients with high expression survived 6 years. UBE2I encodes the sole Sumo-conjugating enzyme in mammalian cells and cells transfected with a dominant-negative sumoylation-deficient UBE2I mutant exhibited decreased survival after radiation exposure, impaired adhesion to bone marrow stroma cell and decreased bone marrow stroma cell-induced proliferation. UBE2I confers cells with multiple advantages to promote tumorigenesis and predicts decreased survival when combined with PIAS1. The sumoylation pathway is a novel therapeutic target with implications for existing proteasomal-based treatment strategies.

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Available from: Dheeraj Pelluru, Jan 10, 2014
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    • "For instance, SUMOylation inhibits cancer establishment through stabilization of tumor suppressor genes or promotes cancer development through stabilization of oncogenes [15,35–43]. Because it is also involved in cellular processes that preserve genomic integrity, such as DNA damage repair, it is thought that aberrancies in SUMOylation possess the ability to promote progression and dissemination, and to initiate therapeutic resistance in cancer cells [44] [45] [46] [47] [48] [49]. "
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    • "The transcription of many of the genes encoding proteins required for sumoylation or desumoylation is altered in tumour cells (reviewed by Bettermann et al. 2012). Examples include: the SUMO protease, SENP1 which is upregulated in thyroid oncocytic adenocarcinoma and human prostate cancer (Cheng et al. 2006b; Jacques et al. 2005), Ubc9 which is upregulated in a wide range of tumours including lung adenocarcinoma (McDoniels-Silvers et al. 2002), ovarian cancer cells (Mo et al. 2005), melanoma-infiltrated lymph nodes, and head and neck cancers (reviewed by Mo and Moschos 2005), and the SUMO ligases PIAS1 where mRNA levels are increased in human prostate cancer (Hoefer et al. 2012) and multiple myeloma (Driscoll et al. 2010) and PIAS3, where levels are increased in breast, lung, prostate, colorectal and brain tumours (Wang and Banerjee 2004). Whether the increased transcription is a result of the transformation or contributes to the cause remains to be determined. "
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