Regulation of HPV16 E6 and MCL1 by SF3B1 inhibitor in head and neck cancer cells.

Regulation of HPV16 E6 and MCL1 by SF3B1 inhibitor in head and neck cancer cells.
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DOI:
10.1038/srep06098
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发表时间:
2014-08-20
期刊:
影响因子:
4.6
通讯作者:
Koide K
Koide K
中科院分区:
综合性期刊3区
文献类型:
--
作者:
Gao Y;Trivedi S;Ferris RL;Koide K

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ABT-737 inhibits the anti-apoptotic proteins B-cell lymphoma 2 (BCL-2) and BCL-XL. Meayamycin B switches the splicing pattern of myeloid cell leukemia factor 1 (MCL1) pre-mRNA. Specifically, inhibition of splicing factor 3B subunit 1 (SF3B1) with meayamycin B promotes the generation of the proapoptotic, short splicing variant (MCL1-S) and diminishes the antiapoptotic, long variant (MCL1-L). This action was previously associated with the cytotoxicity of meayamycin B in non-small cell lung carcinoma cell lines. ABT-737 induced apoptosis in response to an ablation of MCL1-L by meayamycin B. In this study, we further exploited this synergistic combination in head and neck squamous cell carcinoma (HNSCC), up to 90% of which overexpress MCL1 and BCL-XL. In a panel of seven HNSCC cell lines, the combination of meayamycin B and ABT-737 rapidly triggered a Bax/Bak-mediated apoptosis that overcame the resistance from HPV16-positive HNSCC against each agent alone. Both RT-PCR and Western blotting showed that meayamycin B up-regulated MCL1-S and down-regulated MCL1-L. Significantly, we discovered that SF3B1 was involved in the splicing of oncogenic HPV16 E6 to produce non-oncogenic HPV16 E6*, indicating that SF3B1 may inhibit HPV16-induced tumorigenesis.
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