Abstract
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.
Highlights
Neuroblastoma is an embryonic tumour of the sympathetic nervous system derived from precursor or immature cells, and it accounts for 9%-15% of all deaths in children
We report for the first time that the Lamin A/C gene undergoes CpG island promoter hypermethylation-associated gene silencing in a subset of neuroblastoma cells
It has been previously shown that Lamin A/C is silenced by hypermethylation-associated inactivation in human hematologic malignancies [41] (Fig 1A)
Summary
Neuroblastoma is an embryonic tumour of the sympathetic nervous system derived from precursor or immature cells, and it accounts for 9%-15% of all deaths in children. It has recently been shown that knockdown of Lamin A/C expression in neuroblastoma cells inhibits cell differentiation and gives rise to a more aggressive and drug-resistant tumour phenotype [3]. Knockdown of Lamin A/C triggers the development of a human neuroblastoma tumour-initiating cell population with selfrenewing features, predisposing this population to a more immature phenotype with enhanced stem cell characteristics [4]. HGPS patients express the mutant lamin Progerin generated by a silent point mutation (C1824T) in the Lamin A/C gene. This mutation activates a cryptic splice site and generates a form of lamin A with a deletion of 50 amino acids near the C-terminus.
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