RESUMO
Tumor suppressor p53 prevents cell transformation by inducing apoptosis and other responses. Homozygous TP53 deletion occurs in various types of human cancers for which no therapeutic strategies have yet been reported. TCGA database analysis shows that the TP53 homozygous deletion locus mostly exhibits co-deletion of the neighboring gene FXR2, which belongs to the Fragile X gene family. Here, we demonstrate that inhibition of the remaining family member FXR1 selectively blocks cell proliferation in human cancer cells containing homozygous deletion of both TP53 and FXR2 in a collateral lethality manner. Mechanistically, in addition to its RNA-binding function, FXR1 recruits transcription factor STAT1 or STAT3 to gene promoters at the chromatin interface and regulates transcription thus, at least partially, mediating cell proliferation. Our study anticipates that inhibition of FXR1 is a potential therapeutic approach to targeting human cancers harboring TP53 homozygous deletion.
Assuntos
Regulação Neoplásica da Expressão Gênica , Homozigoto , Neoplasias/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Deleção de Sequência , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Sequência de Bases , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Cromatina , Feminino , Edição de Genes , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Inibidores de Janus Quinases/análise , Camundongos , Camundongos Endogâmicos BALB C , Regiões Promotoras Genéticas , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Fatores de TranscriçãoRESUMO
The HIPPO pathway is an evolutionary conserved regulator of organ size that controls both cell proliferation and death. This pathway has an important role in mediating cell death in response to oxidative stress through the inactivation of Yes-associated protein (YAP) and inhibition of anti-oxidant gene expression. Cells exposed to oxidative stress induce the phosphorylation of the alpha (α) subunit of the translation initiation factor eIF2 at serine 51 (eIF2αP), a modification that leads to the general inhibition of mRNA translation initiation. Under these conditions, increased eIF2αP facilitates the mRNA translation of activating transcription factor 4 (ATF4), which mediates either cell survival and adaptation or cell death under conditions of severe stress. Herein, we demonstrate a functional connection between the HIPPO and eIF2αP-ATF4 pathways under oxidative stress. We demonstrate that ATF4 promotes the stabilization of the large tumor suppressor 1 (LATS1), which inactivates YAP by phosphorylation. ATF4 inhibits the expression of NEDD4.2 and WWP1 mRNAs under pro-oxidant conditions, which encode ubiquitin ligases mediating the proteasomal degradation of LATS1. Increased LATS1 stability is required for the induction of cell death under oxidative stress. Our data reveal a previously unidentified ATF4-dependent pathway in the induction of cell death under oxidative stress via the activation of LATS1 and HIPPO pathway.