RESUMO
RNA-binding proteins (RBPs) have garnered significant attention in the field of cancer due to their ability to modulate diverse tumor traits. Once considered untargetable, RBPs have sparked renewed interest in drug development, particularly in the context of RNA-binding modulators of translation. This review focuses on one such modulator, the protein CSDE1, and its pivotal role in regulating cancer hallmarks. We discuss context-specific functions of CSDE1 in tumor development, its mechanisms of action, and highlight features that support its role as a molecular adaptor. Additionally, we discuss the regulation of CSDE1 itself and its potential value as biomarker and therapeutic target.
RESUMO
Oncogene-induced senescence (OIS) is a form of stable cell-cycle arrest arising in response to oncogenic stimulation. OIS must be bypassed for transformation, but the mechanisms of OIS establishment and bypass remain poorly understood, especially at the post-transcriptional level. Here, we show that the RNA-binding protein UNR/CSDE1 enables OIS in primary mouse keratinocytes. Depletion of CSDE1 leads to senescence bypass, cell immortalization, and tumor formation, indicating that CSDE1 behaves as a tumor suppressor. Unbiased high-throughput analyses uncovered that CSDE1 promotes OIS by two independent molecular mechanisms: enhancement of the stability of senescence-associated secretory phenotype (SASP) factor mRNAs and repression of Ybx1 mRNA translation. Importantly, depletion of YBX1 from immortal keratinocytes rescues senescence and uncouples proliferation arrest from the SASP, revealing multilayered mechanisms exerted by CSDE1 to coordinate senescence. Our data highlight the relevance of post-transcriptional control in the regulation of senescence.