SMYD3 overexpression

SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC.

Histone methyltransferase activity and transcription-potentiating function of SMYD3 were found to be essential for tumorigenesis and the SMYD3-HMGA2 is a potential therapeutic target in OSCC.

Important leads for potential pharmaceutical agents have been reported for SMYD2 and SMYD3 enzymes, and six epigenetic inhibitors have been developed for drugs used to treat myelodysplastic syndrome (Vidaza, Dacogen), cutaneous T-cell lymphoma (Zoinza, Isrodax), and peripheral T-cell lymphoma (Beleodag, Epidaza). The recently demonstrated reversal of SMYD histone methylation suggests that reversing the epigenetic effects of SMYDs in cancerous tissues may be a desirable target for pharmacological development.

Increased SMYD3 expression was positively associated with LNM (OR = 1.88, 95% CI = 1.33-2.66, p < 0.001), tumor size (OR = 1.68, 95% CI: 1.09-2.60, p = 0.019), and advanced TNM stage (OR = 1.84, 95% CI: 1.25-2.69, p = 0.002). Upregulation of SMYD3 was significantly associated with poor prognosis in various cancers, suggesting that SMYD3 may be a useful prognostic biomarker.

To study the effect of SMYD3 inhibition on the HR pathway, I treated cells with a SMYD3i and/or Olaparib for 72h and assessed cell death response in single and dual treatments...Conclusion Devising a therapeutic approach for gastric tumors expressing high levels of SMYD3; based on combined treatment with SMYD3 and PARP inhibitors, could have multiple benefits. In particular, it might help mitigating potential drug toxicity by lowering the overall dose needed, while concomitantly promoting GC sensitization.

An in-depth understanding of these processes may be useful to devise novel therapeutical approaches based on the combined pharmacological inhibition of SMYD3 and its newly identified interactors, which may have a synergistic pro-oncogenic effect (e.g., MET). Indeed, this strategy may prove more effective by targeting distinct biological functions of cancer cells, such as DNA damage checkpoints (with SMYD3i) and cancer metabolism (with compounds targeting the AMPK/mTOR axis).

Still, these findings could be useful to devise novel therapeutic strategies based on the combined inhibition of SMYD3 and its newly identified molecular partners. Of note, our in silico methodology may be useful to search for unidentified interactors of other proteins of interest.

Notably, miR-10a-5p mimic-modified HGC-27 exo enhanced the viability, migration and tube formation ability of HUVECs, but this effect was impaired after up-regulating ZMYND11. In summary, miR-10a-5p from GC cells-derived exo enhances viability and migration of HUVECs by suppressing ZMYND11.

Moreover, mRNA SMYD3 expression was observed in 73.3% of GBC and 10% of control (p < 0.05). Our results indicated that the overexpression of SMYD3 plays an important role in the GBC progression, and SMYD3 may represent useful biomarker for gallbladder cancer patients.