Ubiquitination, an important type of
protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various
proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the
protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of
cancer. In
tumorigenesis, the altered biological processes involve
tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to
tumor metabolism, the ubiquitination of some key
proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the
mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and
STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the
proteasome, E3
ligases, E1, E2 and
deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat
cancer. Among them, small molecule inhibitors targeting the
proteasome, such as
bortezomib,
carfilzomib,
oprozomib and
ixazomib, have achieved tangible success. In addition,
MLN7243 and
MLN4924 (targeting the E1
enzyme),
Leucettamol A and
CC0651 (targeting the E2
enzyme), nutlin and
MI-219 (targeting the E3
enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical
cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in
tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for
cancer are reviewed, as are the
therapeutic effects of targeted drugs.