What deubiquitinating enzymes, oncogenes, and tumor suppressors actually do: Are current assumptions supported by patient outcomes?

Abstract

Context can determine whether a given gene acts as an oncogene or a tumor suppressor. Deubiquitinating enzymes (DUBs) regulate the stability of many components of the pathways dictating cell fate so it would be expected that alterations in the levels or activity of these enzymes may have oncogenic or tumor suppressive consequences. In the current review we survey publications reporting that genes encoding DUBs are oncogenes or tumor suppressors. For many DUBs both claims have been made. For such “double agents,” the effects of gain or loss of function will depend on the overall status of a complex of molecular signaling networks subject to extensive crosstalk. As the TGF‐β paradox makes clear context is critical in cell fate decisions, and the disconnect between experimental findings and patient survival outcomes can in part be attributed to disparities between culture conditions and the microenvironment in vivo. Convincing claims for oncogene or tumor suppressor roles require the documentation of gene alterations in patient samples; survival curves are alone inadequate.

USP28: Oncogene or Tumor Suppressor? A Unifying Paradigm for Squamous Cell Carcinoma

“…Notably, 60% of PIRH2 −/− and p53 −/− compound germline knock out mice developed tumors and lived for a significantly shorter time than PIRH2 −/− or p53 −/− single knock-out animals [112]. The above result reconfirms that the role of E3-ligases or DUBs as oncogenes or tumor-suppressor proteins depend on the cellular context and cancer genetic [114].…”

Emerging Role of Deubiquitinating Enzymes (DUBs) in Melanoma Pathogenesis

“…Does environmental diversity, such as metabolic changes [ 112 ], circulating growth factor levels, changing physical stresses or different angiogenic or inflammatory zones [ 113 , 114 ], or the mutational context as “pilot” [ 59 ] or “transient” mutation, affect the degree of deubiquitination, the expression level of DUBs, and the diversity of the substrates of interest in melanoma? Both the modulation of deubiquitinase activity and targeted substrates contribute to this diaphony affecting cellular fate decisions directly relevant to cancer, hinting that the same DUB can be assigned properties of both oncogenes and tumor suppressors depending on the cellular and environmental context [ 115 , 116 ]. Answering these questions should certainly ameliorate the translational potential of targeting DUBs in advanced and refractory melanoma.…”