Post-translational regulation contributes to the loss of LKB1 expression through SIRT1 deacetylase in osteosarcomas

Presneau, Nadège, Duhamel, L.A., Ye, H., Tirabosco, R., Flanagan, A.M. and Eskandarpour, M. 2017. Post-translational regulation contributes to the loss of LKB1 expression through SIRT1 deacetylase in osteosarcomas. British Journal of Cancer. 117, pp. 398-408. doi:10.1038/bjc.2017.174

TitlePost-translational regulation contributes to the loss of LKB1 expression through SIRT1 deacetylase in osteosarcomas
AuthorsPresneau, Nadège, Duhamel, L.A., Ye, H., Tirabosco, R., Flanagan, A.M. and Eskandarpour, M.
Abstract

background: The most prevalent form of bone cancer is osteosarcoma (OS), which is associated with poor prognosis in case of metastases formation. Mice harbouring liver kinase B1 (LKB1+/−) develop osteoblastoma-like tumours. Therefore, we asked whether loss of LKB1 gene has a role in the pathogenesis of human OS.
methods: Osteosarcomas (n=259) were screened for LKB1 and sirtuin 1 (SIRT1) protein expression using immunohistochemistry and western blot. Those cases were also screened for LKB1 genetic alterations by next-generation sequencing, Sanger sequencing, restriction fragment length polymorphism and fluorescence in situ hybridisation approaches. We studied LKB1 protein degradation through SIRT1 expression. MicroRNA expression investigations were also conducted to identify the microRNAs involved in the SIRT1/LKB1 pathway.
results: Forty-one per cent (106 out of 259) OS had lost LKB1 protein expression with no evident genetic anomalies. We obtained evidence that SIRT1 impairs LKB1 protein stability, and that SIRT1 depletion leads to accumulation of LKB1 in OS cell lines resulting in growth arrest. Further investigations revealed the role of miR-204 in the regulation of SIRT1 expression, which impairs LKB1 stability.
conclusions: We demonstrated the involvement of sequential regulation of miR-204/SIRT1/LKB1 in OS cases and showed a mechanism for the loss of expression of LKB1 tumour suppressor in this malignancy.

KeywordsKeywords: osteosarcoma; LKB1; SIRT1; post-translational regulation; miR-204; gene alteration
JournalBritish Journal of Cancer
Journal citation117, pp. 398-408
ISSN0007-0920
Year2017
PublisherNature Publishing Group
Accepted author manuscriptSIRT1- LKB1 revision BJC.pdf
Digital Object Identifier (DOI)doi:10.1038/bjc.2017.174
Publication dates
Published online20 Jun 2017
Published20 Jun 2017
Published in print25 Jul 2017

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