Ubiquitination and deubiquitination: Implications on cancer therapy

Gunjan Dagar, Rakesh Kumar, Kamlesh K. Yadav, Mayank Singh, Tej K. Pandita

Research output: Contribution to journalReview articlepeer-review

3 Scopus citations

Abstract

The ubiquitin proteasomal system (UPS) represents a highly regulated protein degradation pathway essential for maintaining cellular homeostasis. This system plays a critical role in several cellular processes, which include DNA damage repair, cell cycle checkpoint control, and immune response regulation. Recently, the UPS has emerged as a promising target for cancer therapeutics due to its involvement in oncogenesis and tumor progression. Here we aim to summarize the key aspects of the UPS and its significance in cancer therapeutics. We begin by elucidating the fundamental components of the UPS, highlighting the role of ubiquitin, E1-E3 ligases, and the proteasome in protein degradation. Furthermore, we discuss the intricate process of ubiquitination and proteasomal degradation, emphasizing the specificity and selectivity achieved through various signaling pathways. The dysregulation of the UPS has been implicated in cancer development and progression. Aberrant ubiquitin-mediated degradation of key regulatory proteins, such as tumor suppressors and oncoproteins, can lead to uncontrolled cell proliferation, evasion of apoptosis, and metastasis. We outline the pivotal role of the UPS in modulating crucial oncogenic pathways, including the regulation of cyclins, transcription factors, Replication stress components and DNA damage response. The increasing recognition of the UPS as a target for cancer therapeutics has spurred the development of small molecules, peptides, and proteasome inhibitors with the potential to restore cellular balance and disrupt tumor growth. We provide an overview of current therapeutic strategies aimed at exploiting the UPS, including the use of proteasome inhibitors, deubiquitinating enzyme inhibitors, and novel E3 ligase modulators. We further discuss novel emerging strategies for the development of next-generation drugs that target proteasome inhibitors. Exploiting the UPS for cancer therapeutics offers promising avenues for developing innovative and effective treatment strategies, providing hope for improved patient outcomes in the fight against cancer.

Original languageEnglish
Article number194979
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1866
Issue number4
DOIs
StatePublished - Dec 2023
Externally publishedYes

Keywords

  • DNA damage
  • Deubiquitin enzymes (DUBs)
  • Ubiquitin ligase
  • Ubiquitin proteasomal system (UPS)

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