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Published on: July 20, 2019
NSD proteins in anti-tumor immunity and their therapeutic targeting by protein degraders
Suresh Chava1, Narendra Wajapeyee2,3
1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Alabama, 35233, USA.
Abstract:
Chromatin modifiers, owing to their enzymatic activities and frequent overexpression or hyperactivation in cancer, have emerged as promising therapeutic targets. Among these, the nuclear receptor-binding SET domain (NSD) family of proteins catalyzes lysine methylation-a key histone post-translational modification that is implicated in diverse biological processes, primarily through the regulation of transcription. Previous studies have demonstrated that NSD proteins are often overexpressed, mutated, or involved in chromosomal translocations in both hematologic malignancies and solid tumors, thereby regulating tumor initiation and progression. Motivated by these insights, a range of NSD-targeting agents, including targeted protein degraders such as proteolysis-targeting chimeras (PROTACs), have been developed and have exhibited notable anti-cancer activities. In this review, we provide an overview of the NSD family of protein, highlighting their roles in regulating anti-tumor immunity and their implications for immunotherapy response and resistance. We further assess the current landscape of NSD-targeted protein degrader-based therapeutics and their potential utility as anti-cancer agents.
Insights
Chromatin modifiers like nuclear receptor-binding SET domain (NSD) proteins are key in cancer. New proteolysis-targeting chimeras (PROTACs) targeting NSDs show promise for cancer therapy and improving immunotherapy.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Chromatin modifiers, particularly the nuclear receptor-binding SET domain (NSD) protein family, are crucial in regulating gene transcription via histone methylation.
- NSD proteins are frequently dysregulated in various cancers, driving tumor initiation and progression.
- Dysregulated NSD proteins impact anti-tumor immunity, influencing immunotherapy response and resistance.
Purpose of the Study:
- To review the role of NSD proteins in cancer and their impact on anti-tumor immunity.
- To explore the therapeutic potential of NSD-targeting agents, focusing on proteolysis-targeting chimeras (PROTACs).
Main Methods:
- Literature review of studies on NSD proteins in cancer.
- Analysis of the mechanisms by which NSDs affect anti-tumor immunity and immunotherapy.
- Assessment of current NSD-targeted protein degrader therapeutics.
Main Results:
- NSD proteins are implicated in diverse biological processes and are frequently overexpressed or mutated in malignancies.
- NSD-targeting agents, including PROTACs, have demonstrated significant anti-cancer activities.
- Understanding NSDs' role in immunity is crucial for predicting and overcoming immunotherapy resistance.
Conclusions:
- NSD proteins represent promising therapeutic targets in oncology.
- NSD-targeted protein degraders offer a novel therapeutic strategy with potential in cancer treatment and immunotherapy enhancement.
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