SETD3 (SET Domain Containing 3)

This alleviation of ER stress reduces radiation-induced autophagy and apoptosis, ultimately enhancing NPC cell survival under radiotherapeutic stress. Together, these findings reveal a pivotal role for circSETD3 in promoting NPC radioresistance via PDIA6-mediated modulation of endoplasmic reticulum stress, and they provide a novel mechanistic framework and promising therapeutic target for improving radiotherapy efficacy in NPC.

Furthermore, SETD3 mediates methylation of CHD1 to enhance H3K4me3 epigenetic marks and promote transcriptional activation of TNF-NFκB pathway genes. Collectively, our findings establish CHD1 as a new substrate for SETD3 and reveal a mechanism by which SETD3-mediated dimethylation of CHD1 at K209 promotes tumor progression.

Furthermore, circSETD3 deficiency in CRC triggered a feedback loop through the miR-4667-5p-RASA4 axis which was effectively suppressed by exosomal circSETD3 supplementation. Thus, our findings highlight circSETD3 to be a promising therapeutic target for inhibiting CRC progression and overcoming cetuximab resistance.

Molecular dynamics simulations demonstrated that the unbound and SETD3-bound β-actin peptides display different backbone flexibility and bend-like conformations, highlighting their important role in substrate binding and catalysis. Overall, these findings suggest that reduced backbone flexibility of β-actin prevents the formation of optimal protein-peptide interactions between the enzyme and substrate, highlighting that the backbone flexibility needs to be considered when designing β-actin-based probes and inhibitors of biomedically important SETD3.

In addition to this well-characterized molecular function of SETD3, it has been clearly shown to be involved in multiple biological processes, such as cell differentiation, tumorigenesis and viral infection. Here, we summarize the current knowledge on the roles of SETD3 beyond its histidine methyltransferase activity, and outline its cellular and molecular modes of action, as well as the upstream regulation on SETD3, therefore providing insights for the molecular basis of how SETD3 fine regulates multiple physiological and pathological processes.

Importantly, depletion of SETD3 in NUDT16-deficient cells did not further exacerbate DNA breaks or enhance the sensitivity of cancer cells to IR exposure, suggesting that the NUDT16-SETD3 pathway may play critical roles in the induction of tolerance to radiotherapy. Collectively, these data showed that NUDT16 functions as a key upstream regulator of SETD3 protein stability by reversing the ADP-ribosylation of SETD3, and NUDT16 participates in the resolution of replication stress and facilitates HR repair.

Molecular dynamics simulations show that the Trp79 binding pocket of SETD3 is ideally shaped to accommodate large and hydrophobic Trp79, contributing to the favourable release of water molecules upon binding. Our results demonstrate that the distant Trp79 binding site plays an important role in efficient SETD3 catalysis, contributing to the identification of new SETD3 substrates and development of chemical probes targeting the biomedically important SETD3.

Finally, SETDB1, SETD3, PRDM14, and NSD3 could play an important role in the progression of hepatocellular adenocarcinoma since alterations in these genes lead to a decrease in patient survival, unlike patients who present these genes without genetic alterations. Our computational analysis provides new insights that help to understand how HMTs are associated with hepatocellular carcinoma, as well as provide a basis for future experimental investigations using HMTs as genetic targets against hepatocellular carcinoma.

Through RNA sequencing of both patients and cell lines, we established a comprehensive compendium of circRNAs and identified those deregulated in mCRC. This provides a valuable resource for further experimental characterization of circRNAs function in mCRC progression.

Knockdown of miR-653 decreased the effects of hypoxia on CRC cell proliferation, migration and invasion. Taken together, these findings indicated that circSETD3/miR-653/KLF6 axis may be an effective therapeutic target for CRC patients.

CircSETD3/FXR1/ECT2 axis plays a critical role in the acquired resistance to gefitinib in NSCLC. Our results highlight the potential of circSETD3 as a biomarker and therapeutic target for NSCLC patients with acquired gefitinib resistance.