SMYD3 promotes endometrial cancer through epigenetic regulation of LIG4/XRCC4/XLF complex in non-homologous end joining repair

Abstract Endometrial cancer (EC) is one of the most common malignant tumors of female genital tract with rapid increased incidence worldwide. Histone methyltransferase SMYD3, which is linked to the development and progression of various cancers, however, its oncogenic function in endometrial cancer has not been investigated thus far. In the present study, we report that the expression level of SMYD3 is significantly upregulated in EC samples and associated with EC progression. In vivo and in vitro functional experiments demonstrate that SMYD3 depletion inhibits cell proliferation, migration, and invasion abilities, increasing the sensitivity of EC cells to radiation. Moreover, with pathway enrichment analysis, we find that the DNA damage repair pathway is mainly involved in regulating EC progression. Mechanically, in response to DNA damage, SMYD3 is recruited to DNA damage sites in an PARP1-dependent manner and specifically methylates LIG4. Methylated LIG4 sequentially assembles LIG4/XRCC4/XLF complex and participates in non-homologous end joining repair (NHEJ) pathway. More importantly, pharmacological targeting of SMYD3 with its specific inhibitor BCI-121, significantly represses the tumorigenicity of EC cells and greatly enhanced radiotherapy efficiency. Overall, our data suggest SMYD3 as a pivotal factor in NHEJ repair and is associated with in EC progression. Using in vitro and in vivo system, we also prove that SMYD3 is a promising pharmacological target for endometrial cancer therapy.