Cancer cells exhibit unique metabolic features and take advantage of them to enhance their survival and proliferation. While the activation of NRF2 (nuclear factor erythroid 2-like 2; NFE2L2), a CNC (cap'n'collar) family
transcription factor, is effective for the prevention and alleviation of various diseases, NRF2 contributes to
cancer malignancy by promoting aggressive
tumorigenesis and conferring therapeutic resistance. NRF2-mediated metabolic reprogramming and increased
antioxidant capacity underlie the malignant behaviors of NRF2-activated
cancer cells. Another member of the CNC family, NRF1, plays a key role in the therapeutic resistance of
cancers. Since NRF1 maintains
proteasome activity by inducing
proteasome subunit genes in response to
proteasome inhibitors, NRF1 protects
cancer cells from proteotoxicity induced by anticancer
proteasome inhibitors. An important metabolite that activates NRF1 is
UDP-GlcNAc (
uridine diphosphate N-acetylglucosamine), which is abundantly generated in many
cancer cells from
glucose and
glutamine via the
hexosamine pathway. Thus, the metabolic signatures of
cancer cells are closely related to the oncogenic and
tumor-promoting functions of CNC family members. In this review, we provide a brief overview of NRF2-mediated
cancer malignancy and elaborate on NRF1-mediated drug resistance affected by an oncometabolite
UDP-GlcNAc.