DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective

SIMPLE SUMMARY: The transformation of a normal cell into a cancerous one is caused by the deregulation of different metabolic pathways, involving a complex network of protein–protein interactions. The cellular enzymes DDX3X and DDX5 play important roles in the maintenance of normal cell metabolism, but their deregulation can accelerate tumor transformation. Both DDX3X and DDX5 interact with hundreds of different cellular proteins, and depending on the specific pathways in which they are involved, both proteins can either act as suppressors of cancer or as oncogenes. In this review, we summarize the current knowledge about the roles of DDX3X and DDX5 in different tumors. In addition, we present a list of interacting proteins and discuss the possible contribution of some of these protein–protein interactions in determining the roles of DDX3X and DDX5 in the process of cancer proliferation, also suggesting novel hypotheses for future studies. ABSTRACT: RNA helicases of the DEAD-box family are involved in several metabolic pathways, from transcription and translation to cell proliferation, innate immunity and stress response. Given their multiple roles, it is not surprising that their deregulation or mutation is linked to different pathological conditions, including cancer. However, while in some cases the loss of function of a given DEAD-box helicase promotes tumor transformation, indicating an oncosuppressive role, in other contexts the overexpression of the same enzyme favors cancer progression, thus acting as a typical oncogene. The roles of two well-characterized members of this family, DDX3X and DDX5, as both oncogenes and oncosuppressors have been documented in several cancer types. Understanding the interplay of the different cellular contexts, as defined by the molecular interaction networks of DDX3X and DDX5 in different tumors, with the cancer-specific roles played by these proteins could help to explain their apparently conflicting roles as cancer drivers or suppressors.