Open AccessSIX1 represses senescence and promotes SOX2-mediated cellular plasticity during tumorigenesis
Author(s) -
Cristina De Lope,
Samara Martín-Alonso,
Jaione Auzmendi-Iriarte,
Carmen Escudero,
Isabel Mulet,
Javier Larrasa-Alonso,
Irene LópezAntona,
Ander Matheu,
Ignacio Palmero
Publication year - 2019
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-018-38176-0
Subject(s) - senescence , carcinogenesis , biology , psychological repression , repressor , transcriptome , sox2 , phenotype , cancer research , microbiology and biotechnology , regulator , somatic cell , microrna , transcription factor , gene , genetics , gene expression
Six1 is a developmental transcriptional regulator frequently overexpressed in human tumors. Recent results show that SIX1 also acts as a repressor of cell senescence, an antiproliferative response with a key role in tumor suppression, among other physiological and pathological settings. Here, we set to study the impact of SIX1 gain of function in transformation and tumorigenesis of fibroblasts, in connection with senescence. Using transcriptomic, histological, and functional analyses in murine tumors and cells of fibroblast origin, we show that SIX1 has a strong pro-tumorigenic action in this model, linked to the repression of a senescence-related gene signature and the induction of an undifferentiated phenotype mediated, at least in part, by the regulation of the stemness factor Sox2. Moreover, functional analyses with human glioma cell lines also show that SIX1 controls SOX2 expression, senescence and self-renewal in this model. Collectively, our results support a general link of SIX1 with senescence and SOX2-mediated cell plasticity in tumors.