Reference

junio15Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Nat. Med. in press (2015)

Authors

Miguel Vizoso, Humberto J Ferreira, Paula Lopez-Serra, F Javier Carmona, Anna Martínez-Cardús,Maria Romina Girotti, Alberto Villanueva, Sonia Guil, Catia Moutinho, Julia Liz, Anna Portela,Holger Heyn, Sebastian Moran, August Vidal, Maria Martinez-Iniesta, Jose L Manzano,Maria Teresa Fernandez-Figueras, Elena Elez, Eva Muñoz-Couselo, Rafael Botella-Estrada,Alfonso Berrocal, Fredrik Pontén, Joost van den Oord, William M Gallagher, Dennie T Frederick,Keith T Flaherty, Ultan McDermott, Paul Lorigan, Richard Marais y Manel Esteller

Abstract

Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors.

Description

En el presente estudio se ha identificado la reactivación epigenética de una variante génica durmiente en tejidos sanos, íntimamente ligada al proceso de metastatización de los tumores de melanoma. Dicha modificación ha demostrado tener potentes implicaciones en su capacidad de predecir la evolución de los pacientes a la enfermedad y la respuesta a los actuales tratamientos que se suministran actualmente en la clínica.

fotojulio2015

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Epigenética del Cáncer del Instituto de Investigación Biomédica de Bellvitge (IDIBELL) dirigido por el Dr. Manel Esteller tiene como objetivo la investigación de las alteraciones de la metilación del DNA, las modificaciones de histonas y el RNA no codificante de proteínas (ncRNAs), para encontrar la relación de estos fenómenos con el desarrollo del cáncer en humanos. En concreto el investigador Miguel Vizoso se centra en el estudio de marcadores epigenéticos basados en la metilación del ADN que se puedan emplear para una mejor estratificación de los pacientes aquejados de melanoma metastásico así como de desenmascarar los mecanismos moleculares de resistencia generados en los pacientes a los fármacos que se les suministran para combatir la enfermedad.

Descárgate este artículo aquí.

Did you publish an interesting article recently?

Send it through our application form and we will contact you. Age limit: 32.

The selected articles will participate at the Award to the best article of young people of the SEBBM which will be given during SEBBM conference, that will take place at Spain (free registration, travel and accommodation).

More articles of the month

Identification of distinct maturation steps involved in human 40S ribosomal subunit biosynthesis

29-02-2020

Technical problems intrinsic to the purification of preribosome intermediates have limited our understanding of ribosome biosynthesis in humans. Addressing this issue is important given the implication of this biological process...

Read more

Unraveling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis

23-01-2020

B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of...

Read more

Mip6 binds directly to the Mex67 UBA domainto maintain low levels of Msn2/4 stress-dependent mRNAs

23-12-2019

RNA-binding proteins (RBPs) participate in all steps of gene expression, underscoring their potential as regulators of RNA homeostasis. We structurally and functionally characterize Mip6, a four-RNA recognition motif (RRM)-containing RBP...

Read more

A bacterial light response reveals an orphan desaturase for human plasmalogen synthesis

01-12-2019

Plasmalogens are glycerophospholipids with a hallmark sn-1 vinyl ether bond. These lipids are found in animals and some bacteria and have proposed membrane organization, signaling, and antioxidant roles. We discovered...

Read more

The structure of a polygamous repressor reveals how phage-inducible chromosomal islands spread in nature

01-11-2019

Stl is a master repressor encoded by Staphylococcus aureus pathogenicity islands (SaPIs) that maintains integration of these elements in the bacterial chromosome. After infection or induction of a resident helper...

Read more

Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt

01-10-2019

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug delivery system based on elastin-like block recombinamers. The DNA recombinant technics allowed us to create...

Read more

Structure–Function of MamC Loop and Its Effect on the *in Vitro* Precipitation of Biomimetic Magnetite Nanoparticles

01-09-2019

MamC, an integral protein of the magnetosome membrane, has recently been proposed as a strong candidate to produce biomimetic (magnetosome-like) magnetite nanoparticles that could be used as an alternative to...

Read more

Sticholysin, Sphingomyelin, and Cholesterol: A Closer Look at a Tripartite Interaction

01-08-2019

Actinoporins are a group of soluble toxic proteins that bind to membranes containing sphingomyelin (SM) and oli- gomerize to form pores. Sticholysin II (StnII) is a member of the actinoporin...

Read more

Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour

01-07-2019

To satisfy its high energetic demand, the brain depends on the metabolic cooperation of various cell types. For example, astrocytic-derived lactate sustains memory consolidation by serving both as an oxidizable...

Read more

Glucose restriction promotes osteocyte specification by activating a PGC-1α-dependent transcriptional program

03-06-2019

Osteocytes, the most abundant of bone cells, differentiate while they remain buried within the bone matrix. This encasement limits their access to nutrients and likely affects their differentiation, a process...

Read more

Protector Members