The next decade of SET: from an oncoprotein to beyond

Abstract

This year marks the fourth decade of research into the protein SET, which was discovered in 1992. SET was initially identified as an oncoprotein but later shown to be a multifaceted protein involved in regulating numerous biological processes under both physiological and pathophysiological conditions. SET dysfunction is closely associated with diseases, such as cancer and Alzheimer's disease. With the increasing understanding of how SET works and how it is regulated in cells, targeting aberrant SET has emerged as a potential strategy for disease intervention. In this review, we present a comprehensive overview of the advancements in SET studies, encompassing its biological functions, regulatory networks, clinical implications, and pharmacological inhibitors. Furthermore, we provide insights into the future prospects of SET research, with a particular emphasis on its promising potential in the realm of immune modulation.

Keywords: SET; biological process; disease; regulatory mechanism; therapy.

Figure 1

The timeline and milestones of the studies on the SET protein. The timeline starts with the identification of SET as an oncogene in the early 1990s and continues through recent studies on its role in cancer initiation and progression.

Figure 2

The structural features and expression patterns of SET. The SET protein maintains highly conserved structural features, consisting of an N-terminal DD, an ED, and a C-terminal AD. The phosphorylation of Ser9 in the AD is associated with the depolymerization of the SET protein dimer and its redistribution at the plasma membrane. The ED is involved in histone assembly. The AD mediates the interaction between SET and other proteins. In addition, SET primarily localizes in the nucleus and cytoplasm and is widely expressed in different diseases, such as lung cancer, colon cancer, kidney cancer, breast cancer, prostate cancer, and Alzheimer's disease. Ac, acetylation; P, phosphorylation.

Figure 3

SET-mediated regulation of biological processes. SET is a multifunctional protein that regulates numerous physiological processes, including transcription, DNA repair, cell cycle, apoptosis, and cell metastasis. These processes are often mediated by the interaction of SET with other proteins, such as p53, FOXO1, KLF5, KAP1, KU70/80, NM23-H1, and Rac1. Ac, acetylation; P, phosphorylation.

Figure 4

Intracellular regulation of SET. The regulation of SET in response to cellular stimuli can be achieved at multiple layers, including transcription, posttranscription, and posttranslation. Ac, acetylation.

Figure 5

SET antagonists targeting the SET–PP2Ac interaction. SET antagonists that disrupt the interaction between SET and PP2A have the potential as cancer therapeutics. Targeting SET by FTY720/ceramide, COG112/OP449, or EMQA reactivates PP2A, which in turn promotes tumor growth suppression and therapeutic resistance defense in a spectrum of various cancer cells. A, the structural subunit of PP2A; B, the regulatory subunit of PP2A; C, the catalytic subunit of PP2A.