Polycomp group (PcG) proteins are members of highly conserved multiprotein complexes, recognized as gene transcriptional repressors during development and shown to play a role in various physiological and pathological processes. PcG proteins consist of two Polycomb repressive complexes (PRCs) with different enzymatic activities: Polycomb repressive complexes 1 (PRC1), a ubiquitin ligase, and Polycomb repressive complexes 2 (PRC2), a histone methyltransferase. Traditionally, PRCs have been described to be associated with transcriptional repression of homeotic genes, as well as gene transcription activating effects. Particularly in cancer, PRCs have been found to misregulate gene expression, not only depending on the function of the whole PRCs, but also through their separate subunits. In this review, we focused especially on the recent findings in the transcriptional regulation of PRCs, the oncogenic and tumor-suppressive roles of PcG proteins, and the research progress of inhibitors targeting PRCs.

Liver fibrosis is a very common health problem and currently lacks effective treatments. Cullin RING E3 ligases (CRLs) regulate the turnover of ∼20% of mammalian cell proteins. Neddylation, the process by which NEDD8 is covalently attached to cullin proteins through sequential enzymatic reactions, is critical for the activation of CRLs and was recently found to be elevated in liver fibrosis. NEDD8-activating enzyme E1-specific inhibition led to the reduced liver damage characterized by decreased apoptosis, inflammation, and fibrosis. However, the relevance of a co-E3 ligase, DCN1, in liver fibrosis remains unclear. Here, a novel and potent DCN1–UBC12 interaction inhibitor HZX-960 was discovered with an IC₅₀ value of 9.37 nmol/L, which could inhibit the neddylation of cullin3. Importantly, we identified that HZX-960 treatment could attenuate transforming growth factor β-induced liver fibrotic responses by reducing the deposition of collagen I and α-smooth muscle actin, and upregulating cellular NF-E2-related factor 2, hemeoxygenase 1, and NADPH quinone oxidoreductase-1 levels in two hepatic stellate cell lines. Additionally, DCN1 was shown to be unregulated in CCl₄-induced mice liver tissue, and liver fibrotic signaling in mice was reduced by HZX-960. Therefore, our data demonstrated that HZX-960 possessed anti-liver fibrosis ability and that DCN1 may be a potential therapeutic target for liver fibrosis treatment.

Proteolysis targeting chimeras (PROTACs) have emerged as an intriguing therapeutic strategy for targeted protein degradation (TPD), functioning as heterobifunctional compounds that induce the redirection of E3 ligases to ubiquitinate neo‐substrates for proteasomal degradation. Despite the presence of over 600 E3 ligases, only a limited subset has been successfully harnessed for TPD. This study demonstrates that S‐phase kinase‐associated protein 2 (SKP2), the substrate receptor of the Cullin RING ligase 1 (CRL1) subfamily, can be employed for TPD using a selective, non‐covalent SKP2 recruiter, SL1 . We designed and synthesized SKP2‐recruiting degraders by linking SL1 to the BRD4 inhibitor JQ1 . These compounds effectively induce BRD4 degradation in MV‐4‐11 cells, with the most potent compound 2‐1 exhibiting a half‐maximal degradation (DC ₅₀ ) of 298 nM, validating their potential as PROTACs. Mechanistic investigations show that 2‐1 promotes BRD4 ubiquitination and subsequent degradation in a proteasome‐ and neddylation‐dependent manner, which can be rescued by SKP2 knockdown and knockout. We further demonstrate that SKP2‐directed PROTACs effectively degrade Androgen receptor (AR) in 22RV1 cells. These findings emphasize that SKP2, frequently overexpressed in various tumor cells, can be successfully exploited for TPD through non‐covalent PROTACs, expanding the pool of E3 ligases available for potential therapeutic applications.