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Promoter hypermethylation as a mechanism for Lamin A/C silencing in a subset of neuroblastoma cells.

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.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 28422997
OWN - NLM
STAT- In-Process
DA  - 20170419
LR  - 20170419
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - Promoter hypermethylation as a mechanism for Lamin A/C silencing in a subset of
      neuroblastoma cells.
PG  - e0175953
LID - 10.1371/journal.pone.0175953 [doi]
AB  - 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 Delta50, 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.
FAU - Rauschert, Ines
AU  - Rauschert I
AD  - Laboratory of Cellular Signaling and Nanobiology, Instituto de Investigaciones
      Biologicas Clemente Estable, Montevideo, Uruguay.
FAU - Aldunate, Fabian
AU  - Aldunate F
AD  - Epigenetics of Cancer and Aging Laboratory, Institut Pasteur de Montevideo,
      Montevideo, Uruguay.
FAU - Preussner, Jens
AU  - Preussner J
AD  - Bioinformatics Core Unit (BCU), Max Planck Institute for Heart and Lung Research,
      Bad Nauheim, Germany.
FAU - Arocena-Sutz, Miguel
AU  - Arocena-Sutz M
AD  - Epigenetics of Cancer and Aging Laboratory, Institut Pasteur de Montevideo,
      Montevideo, Uruguay.
FAU - Peraza, Vanina
AU  - Peraza V
AD  - Epigenetics of Cancer and Aging Laboratory, Institut Pasteur de Montevideo,
      Montevideo, Uruguay.
FAU - Looso, Mario
AU  - Looso M
AD  - Bioinformatics Core Unit (BCU), Max Planck Institute for Heart and Lung Research,
      Bad Nauheim, Germany.
FAU - Benech, Juan C
AU  - Benech JC
AD  - Laboratory of Cellular Signaling and Nanobiology, Instituto de Investigaciones
      Biologicas Clemente Estable, Montevideo, Uruguay.
FAU - Agrelo, Ruben
AU  - Agrelo R
AUID- ORCID: http://orcid.org/0000-0002-3142-9286
AD  - Epigenetics of Cancer and Aging Laboratory, Institut Pasteur de Montevideo,
      Montevideo, Uruguay.
LA  - eng
PT  - Journal Article
DEP - 20170419
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
EDAT- 2017/04/20 06:00
MHDA- 2017/04/20 06:00
CRDT- 2017/04/20 06:00
PHST- 2016/11/12 [received]
PHST- 2017/04/03 [accepted]
AID - 10.1371/journal.pone.0175953 [doi]
AID - PONE-D-16-44991 [pii]
PST - epublish
SO  - PLoS One. 2017 Apr 19;12(4):e0175953. doi: 10.1371/journal.pone.0175953.
      eCollection 2017.

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