Regulators of carcinogenesis: Emerging roles beyond their primary functions

Cancers are characterized by aberrant cell signaling that results in accelerated proliferation, suppressed cell death, and reprogrammed metabolism to provide sufficient energy and intermediate metabolites for macromolecular biosynthesis. Here, we summarize the emerging “unconventional” roles of these regulators based on their newly identified interaction partners, different subcellular localizations, and/or structural variants. For example, the epidermal growth factor receptor (EGFR) regulates DNA synthesis, microRNA maturation and drug resistance by interacting with previously undescribed partners; cyclins and cyclin-dependent kinases (CDKs) crosstalk with multiple canonical pathways by phosphorylating novel substrates or by functioning as transcriptional factors; apoptosis executioners play extensive roles in necroptosis, autophagy, and in the self-renewal of stem cells; and various metabolic enzymes and their mutants control carcinogenesis independently of their enzymatic activity. These recent findings will supplement the systemic functional annotation of cancer regulators and provide new rationales for potential molecular targeted cancer treatments.