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RNA binding proteins and cancer progression

RNA binding proteins and cancer progressionRNA binding proteins and cancer progression

RNA-binding proteins (RBPs) orchestrate RNA fate and function. RBPs have been shown to modulate virtually all cancer hallmarks and are emerging as critical regulators of oncogenic cell transformation, malignancy and therapy resistance. We are interested in RBPs that facilitate cancer cell resistance to stress, especially those contributing to translational reprogramming. We aim to understand how they function, dissect their regulatory networks, and use this knowledge to identify robust biomarkers and therapeutic targets. 

We work with canonical and non-canonical RBPs (i.e. those without discernible RNA binding domains) that are directly or indirectly involved in mRNA translation. We use a combination of high-throughput technologies (RNA interactome capture, RNA-seq, iCLIP, Ribo-Seq, polysome-Seq, proteomics) to address our questions using melanoma as a tumor model. Most of our efforts are concentrated on four proteins:
 


 

  • CSDE1: 

Cold Shock Domain protein E1 (CSDE1) is a conserved RBP that has context-specific functions in cancer. We worked in the past with the CSDE1 homologue in Drosophila (called UNR) and showed that it exerts sex-specific functions in development, particularly in the process of X-chromosome dosage compensation. This was explained by interaction of UNR with sex-specific mRNA targets or co-factors (e.g. Hennig et al., 2014; Militti et al., 2014; Szostak et al., 2018). In the cancer context, we have shown that CSDE1 functions as an oncoprotein in melanoma and as a tumor suppressor in squamous cell carcinoma (Wurth et al., 2016; Avolio et al., 2022). These opposing roles of CSDE1 are explained, at least in part, by differences in translation regulation, and we are currently exploring the underlying mechanisms. In addition, we are testing the value of CSDE1 as biomarker in partnership with our clinician collaborators. 

Hennig et al., Nature 2014. doi: 10.1038/nature13693
Militti et al., Nat Commun 2014. doi: 10.1038/ncomms5762
Szostak et al., Nucleic Acids Res 2018. doi: 10.1093/nar/gky246
Wurth et al., Cancer Cell 2016. doi: 10.1016/j.ccell.2016.10.004
Avolio et al., Cell Reports 2022. doi: 10.1016/j.celrep.2021.110211

  • PDIA6:

Protein Disulfide Isomerase Family A Member 6 (PDIA6) is a protein chaperone residing in the ER lumen with a reported role in the UPR stress response. We have recently found that PDIA6 is also an unconventional RBP (Mestre-Farrás et al., 2022). This is quite intriguing given the intracellular localization of PDIA6, and suggests a facet of PDIA6 still to be explored. We are interested in identifying PDIA6 RNA targets and RNA-dependent protein partners, and in understanding how RNA intersects with the biology of PDIA6. 

Mestre-Farrás et al., Nucleic Acids Res 2022. doi: 10.1093/nar/gkac605

  • PABC5:

Poly(A)-binding protein C5 (PABPC5) is a rare, distant member of the PABPC family whose function is poorly understood. We came across this protein on a recent screen for RBPs with potential roles in melanoma progression and are currently investigating its involvement and mechanisms (Mestre-Farrás et al., 2022).

Mestre-Farrás et al., Nucleic Acids Res 2022. doi: 10.1093/nar/gkac605

  • eIF2A:

Eukaryotic Translation Initiation Factor 2A (eIF2A, please do not confuse with eIF2a/eFI2S1) is an alternative translation initiation factor that is thought to function in situations of stress, when its canonical counterpart eIF2a is inhibited. A recent screen identified eIF2A as an RBP with potential roles in melanoma progression and we are currently investigating its involvement and mechanisms (Mestre-Farrás et al., 2022).

Mestre-Farrás et al., Nucleic Acids Res 2022. doi: 10.1093/nar/gkac605