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KMID : 1140120110160020093
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Cancer Prevention Research
2011 Volume.16 No. 2 p.93 ~ p.101
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Structural Insight into the Post-SET Loop Conformation of NSD1 Implications for the Epigenetic Therapy of Cancers Targeting Histone Lysine Methyltransferases
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di Luccio Eric
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Abstract
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Both genetic and epigenetic alterations are responsible for the stepwise initiation and progression of cancers. Only epigenetic aberrations can be reversible, allowing the malignant cell population to revert to a more benign phenotype. The epigenetic therapy of cancers is emerging as an effective and valuable approach to both chemotherapy and the chemoprevention of cancer. The utilization of epigenetic targets that include histone methyltransferase (HMTase), histone deacetylase, and DNA methyltransferase, are emerging as key therapeutic targets. The nuclear receptor binding SET domain (NSD) protein is a family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1, and plays a critical part in chromatin integrity as evidenced by a growing number of conditions linked to the alterations or amplification of NSD1, NSD2, or NSD3. NSD1, NSD2 and NSD3 are associated with multiple cancers. The amplification of either NSD1 or NSD2 triggers the cellular transformation and thus is key in the early carcinogenesis events. In most cases, reducing the levels of NSDs would suppress cancer growth. The NSD pathways, however, are not well understood. Recently, a partial crystal structure of the ligandless SET domain of NSD1 has been published enabling further studies toward a structure-based drug design effort on the NSD family. Here, we use computational methods to model the binding of the natural ligand histone H4K20 on the SET domain of NSD1. Our findings unravel a critical insight into an autoregulatory mechanism driven by the flexibility of the post-SET loop region and we prospect its special value for developing novel anticancer drugs.
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KEYWORD
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Transcription factor, Histone methyl transferase, HMTase inhibitor, NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1, Acute myeloid leukemia, Multiple myeloma, Prostate cancer, Breast cancer, Lung cancer, Cellular transformation, Epigenetic cancer therapy
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