Ubiquitination of transcription factors in cancer: unveiling therapeutic potential

Transcription factors, pivotal in gene expression regulation, are essential in cancer progression. Their function is meticulously regulated by post-translational modifications, including ubiquitination. This process, which marks proteins for degradation, can either enhance or inhibit the function of transcription factors, contingent on the context. In cancers, dysregulated ubiquitination of transcription factors contributes to the hallmark of uncontrolled growth and survival of tumors. For example, tumor suppressors such as p53 might be degraded prematurely due to abnormal ubiquitination, causing genomic instability. On the other hand, oncogenic transcription factors may gain stability via ubiquitination, thus facilitating tumorigenesis. Targeting the ubiquitin–proteasome system (UPS) therefore could be a viable therapeutic approach in cancer. Emerging treatments aim to block the ubiquitination of oncogenic transcription factors or to stabilize tumor suppressors. This review underscores the critical impact of transcription factor-altered ubiquitination on cancer progression. Additionally, it outlines innovative therapeutic approaches that involve inhibitors or drugs directed at specific ubiquitin E3 ligases and deubiquitinases (DUBs) that regulate transcription factor activity.