Promoter hypermethylation as a mechanism for Lamin A-C silencing in a subset of neuroblastoma cellsReport as inadecuate

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Nuclear lamins support the nuclear envelope and provide anchorage sites for chromatin. They are involved in DNA synthesis, transcription, and replication. It has previously been reported that the lack of Lamin A-C expression in lymphoma and leukaemia is due to CpG island promoter hypermethylation. Here, we provide evidence that Lamin A-C is silenced via this mechanism in a subset of neuroblastoma cells. Moreover, Lamin A-C expression can be restored with a demethylating agent. Importantly, Lamin A-C reintroduction reduced cell growth kinetics and impaired migration, invasion, and anchorage-independent cell growth. Cytoskeletal restructuring was also induced. In addition, the introduction of lamin Δ50, known as Progerin, caused senescence in these neuroblastoma cells. These cells were stiffer and developed a cytoskeletal structure that differed from that observed upon Lamin A-C introduction. Of relevance, short hairpin RNA Lamin A-C depletion in unmethylated neuroblastoma cells enhanced the aforementioned tumour properties. A cytoskeletal structure similar to that observed in methylated cells was induced. Furthermore, atomic force microscopy revealed that Lamin A-C knockdown decreased cellular stiffness in the lamellar region. Finally, the bioinformatic analysis of a set of methylation arrays of neuroblastoma primary tumours showed that a group of patients around 3% gives a methylation signal in some of the CpG sites located within the Lamin A-C promoter region analysed by bisulphite sequencing PCR. These findings highlight the importance of Lamin A-C epigenetic inactivation for a subset of neuroblastomas, leading to enhanced tumour properties and cytoskeletal changes. Additionally, these findings may have treatment implications because tumour cells lacking Lamin A-C exhibit more aggressive behaviour.

Author: Ines Rauschert , Fabian Aldunate , Jens Preussner, Miguel Arocena-Sutz, Vanina Peraza, Mario Looso, Juan C. Benech , Ruben Agrelo



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