Ubiquitination/de-ubiquitination: A promising therapeutic target for PTEN reactivation in cancer

Tumor suppressor activation or reactivation has long been a sought-after, yet elusive, therapeutic strategy for human cancer. Phosphatase and tensin homolog (PTEN) is one of the most frequently mutated tumor suppressor genes that regulate many biological processes, including proliferation, survival, cellular architecture, motility, energy metabolism, and genomic stability. As a dose-dependent tumor suppressor, subtle reductions in PTEN protein levels and activity will alter the gene-expression profiles involved in tumor progression, laying the foundation for PTEN reactivation in cancer treatment. However, treatment strategies that manipulate and/or replace PTEN activity to successfully block and reverse the destructive progression of cancer are not yet available. Ubiquitination/de-ubiquitination is one of the major regulatory mechanisms of PTEN by influencing its stability, subcellular localization, and activity. Recent discoveries, including new ubiquitination sites, E3 ubiquitin ligases, de-ubiquitinases of PTEN, and participation of accessory and adaptor proteins, have revealed new modes of PTEN ubiquitination regulation. Furthermore, either pharmaceutical or gene-targeted inhibition of E3 ligase-mediated ubiquitination of PTEN potently releases PTEN's anticancer activity and suppresses tumorigenesis. These findings shed light on therapeutic strategies for reactivating PTEN in cancer that target ubiquitination/de-ubiquitination. Therefore, a comprehensive understanding of the ubiquitination/de-ubiquitination regulation of PTEN could help improve clinical conceptualization and treatment of cancer. This review aimed to summarize and discuss recent discoveries on PTEN ubiquitination and de-ubiquitination, with the goal of providing a systematic summary in the field and promoting clinical transformation of targeting ubiquitination for PTEN reactivation in the treatment of cancer.