SND1-SMARCA5 interaction strengthened by PIM promoted the proliferation, metastasis and chemoresistance of ESCC
Chromatin remodeling plays a pivotal role in the progression of esophageal squamous cell carcinoma (ESCC), yet the precise mechanisms remain poorly understood. Here, we elucidate the critical function of staphylococcal nuclease and tudor domain-containing 1 (SND1) in modulating chromatin dynamics, thereby driving ESCC progression in both in vitro and in vivo models. Our data revealed that SND1 was markedly overexpressed in ESCC cell lines. Silencing SND1 disrupted histone modifications, attenuated RNA polymerase II activity, and precipitated increased chromosomal aberrations and DNA damage, particularly following camptothecin treatment. These molecular perturbations culminated in diminished cellular proliferation, metastasis and chemoresistance. We further identified that the regulatory effects of SND1 on chromatin are mediated through its interaction with SMARCA5, a process potentiated by PIM1-catalyzed phosphorylation of SND1 at serine 426. This SND1-SMARCA5 interaction is essential for the transcriptional activation of CUX1, a key oncogene implicated in ESCC progression. Notably, disruption of SND1S426 phosphorylation impaired the SND1-SMARCA5 interaction, leading to significant inhibition of ESCC tumor growth and metastatic potential in vivo. Our findings unveil a novel mechanistic axis involving SND1 and SMARCA5 in chromatin remodeling and oncogenesis, offering promising therapeutic targets for ESCC intervention. Overall design: The influence of SND1 on chromatin remodeling in ESCC cell was evaluated by rna interference, western blot, karyotype assay, laser confocal and ATAC-sequence. Colony formation and cell cycle array were used to evaluate cell proliferation. The metastasis and chemoresistance of ESCC cells were studied by transwell, plate survival and flow cytometry respectively. Xenograft mice and liver metastasis model were used to evaluate the proliferation and metastasis of ESCC. The mechanism of SND1 in ESCC was studied through Co-IP, mass spectrometry, ChIP-qPCR, pull down and laser confocal. The correlation of SND1 and its downstream gene with ESCC were investigated through IHC respectively.