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

Gao, Y and Trivedi, S and Ferris, RL and Koide, K (2014) Regulation of HPV16 E6 and MCL1 by SF3B1 inhibitor in head and neck cancer cells. Scientific Reports, 4.

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ABT-737 inhibits the anti-apoptotic proteins B-cell lymphoma 2 (BCL-2) and BCL-X L. 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-X L. 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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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Gao, Y
Trivedi, S
Ferris, RLrlf1@pitt.eduRLF1
Koide, Kkoide@pitt.eduKOIDE0000-0001-8894-8485
Centers: Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute
Date: 20 August 2014
Date Type: Publication
Journal or Publication Title: Scientific Reports
Volume: 4
DOI or Unique Handle: 10.1038/srep06098
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
Other ID: NLM PMC4138523
PubMed Central ID: PMC4138523
PubMed ID: 25139387
Date Deposited: 12 May 2015 19:53
Last Modified: 15 Feb 2020 15:55


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