Loss of sirtuin SIRT1 promotes aggressiveness of colon adenocarcinoma by modulating voltage-gated sodium channel activity

Sirtuin 1 (SIRT1), a NAD⁺-dependent epigenetic regulator, has been reported as both tumour-promoting and tumour-suppressive in colorectal cancer, leaving its role unclear. We analysed SIRT1 expression in a cohort of 176 colon cancer patients and public datasets, correlating findings with clinical outcomes. Functional studies were performed in human colon cancer cell lines to assess proliferation, invasion, and epithelial-mesenchymal transition (EMT). SIRT1 expression was elevated in primary tumours compared to adjacent mucosa; however, lower intratumoral SIRT1 levels were associated with lymph node metastasis, reduced metastasis-free survival, and decreased overall survival. Transcriptomic analyses revealed progressive SIRT1 downregulation in advanced and metastatic tumours. Functionally, SIRT1 depletion induced EMT and increased invasiveness in both primary and metastatic cell lines. Mechanistically, we identified voltage-gated sodium channels as key effectors. Loss of SIRT1 enhanced SCN5A transcription, increased Na V 1.5 membrane expression, and elevated inward sodium current. Pharmacological inhibition of Na V channels abolished the pro-invasive effects of SIRT1 loss. These findings reveal an epigenetic-electrogenic coupling mechanism in colorectal cancer, where SIRT1 loss promotes Na V -dependent invasion. SIRT1 thus acts as a gatekeeper of metastatic progression and links chromatin regulation to cancer cell invasiveness.