NSD3S Promotes Cell Proliferation Through Stabilizing c‐Myc in Psoriatic Keratinocytes

Histone methyltransferase nuclear receptor binding SET domain protein 3 (NSD3) has been reported to promote cell proliferation in a variety of cancer cells. However, whether NSD3 regulates cell proliferation in psoriatic cells is unknown. Here, we found elevated expression of NSD3S (the short isoform with no activity) but not NSD3L (the long isoform) in psoriatic keratinocytes, and specific knockdown of NSD3S expression decreases cell proliferation of psoriatic keratinocytes. Further investigation has shown that NSD3S knockdown destabilizes c‐Myc protein but does not suppress the transcription of the c‐MYC gene. Notably, a cell‐penetrating peptide TAT‐tagged inhibitory peptide TAT–NSD3 389–404 targeting NSD3–c‐Myc interaction destabilizes c‐Myc protein in a similar way, suggesting that NSD3S stabilizes c‐Myc through interaction. Most importantly, treatment with TAT–NSD3 389–404 peptide alleviates psoriatic symptoms and decreases the Psoriasis Area and Severity Index (PASI) score, the lesion thickness, and the concentration of psoriasis‐related cytokines (IL‐17, IL‐6, and CXCL1) in imiquimod‐induced psoriasis‐like mice, suggesting NSD3–c‐Myc interaction may be a potential therapeutic target for psoriasis.