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Journal of Experimental & Clinical Cancer Research

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01-12-2021 | Seminoma | Research

The component of the m⁶A writer complex VIRMA is implicated in aggressive tumor phenotype, DNA damage response and cisplatin resistance in germ cell tumors

Authors: Vera Miranda-Gonçalves, João Lobo, Catarina Guimarães-Teixeira, Daniela Barros-Silva, Rita Guimarães, Mariana Cantante, Isaac Braga, Joaquina Maurício, Christoph Oing, Friedemann Honecker, Daniel Nettersheim, Leendert H. J. Looijenga, Rui Henrique, Carmen Jerónimo

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Germ cell tumors (GCTs) are developmental cancers, tightly linked to embryogenesis and germ cell development. The recent and expanding field of RNA modifications is being increasingly implicated in such molecular events, as well as in tumor progression and resistance to therapy, but still rarely explored in GCTs. In this work, and as a follow-up of our recent study on this topic in TGCT tissue samples, we aim to investigate the role of N6-methyladenosine (m⁶A), the most abundant of such modifications in mRNA, in in vitro and in vivo models representative of such tumors.

Methods

Four cell lines representative of GCTs (three testicular and one mediastinal), including an isogenic cisplatin resistant subline, were used. CRISPR/Cas9-mediated knockdown of VIRMA was established and the chorioallantoic membrane assay was used to study its phenotypic effect in vivo.

Results

We demonstrated the differential expression of the various m⁶A writers, readers and erasers in GCT cell lines representative of the major classes of these tumors, seminomas and non-seminomas, and we evidenced changes occurring upon differentiation with all-trans retinoic acid treatment. We showed differential expression also among cells sensitive and resistant to cisplatin treatment, implicating these players in acquisition of cisplatin resistant phenotype. Knockdown of VIRMA led to disruption of the remaining methyltransferase complex and decrease in m⁶A abundance, as well as overall reduced tumor aggressiveness (with decreased cell viability, tumor cell proliferation, migration, and invasion) and increased sensitivity to cisplatin treatment, both in vitro and confirmed in vivo. Enhanced response to cisplatin after VIRMA knockdown was related to significant increase in DNA damage (with higher γH2AX and GADD45B levels) and downregulation of XLF and MRE11.

Conclusions

VIRMA has an oncogenic role in GCTs confirming our previous tissue-based study and is further involved in response to cisplatin by interfering with DNA repair. These data contribute to our better understanding of the emergence of cisplatin resistance in GCTs and support recent attempts to therapeutically target elements of the m⁶A writer complex.

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Title: The component of the m6A writer complex VIRMA is implicated in aggressive tumor phenotype, DNA damage response and cisplatin resistance in germ cell tumors
Authors: Vera Miranda-Gonçalves
João Lobo
Catarina Guimarães-Teixeira
Daniela Barros-Silva
Rita Guimarães
Mariana Cantante
Isaac Braga
Joaquina Maurício
Christoph Oing
Friedemann Honecker
Daniel Nettersheim
Leendert H. J. Looijenga
Rui Henrique
Carmen Jerónimo
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Seminoma
Nonseminoma
Seminoma
Nonseminoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-02072-9

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Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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