Pharmacological Activation of SIRT6 Suppresses Progression of Head and Neck and Esophagus Squamous Cell Carcinoma by Modulation of Cellular Metabolism and Protein Translation

Sirtuin 6 (SIRT6), a NAD+ -dependent histone deacetylase, has been shown to function as a tumor suppressor gene in several cancer types, including in squamous cell carcinoma of the head and neck and esophagus (HNSCC and ESCC). However, the potential of therapies involving the activation of SIRT6 in HNSCC and ESCC remains unexplored. In this work, we investigated the therapeutic potential and mechanisms of action of the allosteric SIRT6 activator MDL-800 in HNSCC and ESCC cell lines both in vitro and in vivo . First, we showed that MDL-800 treatment exhibited extensive anti-tumor activity in vitro by inhibiting the proliferation and migration of HNSCC and ESCC cell lines. In cell-derived xenograft mouse models, MDL-800 treatment effectively delayed tumor growth in two cancer models. Mechanistically, using global H3K9ac acetylation profiling, and protein arrays, we demonstrated that MDL-800 treatment potently inhibits glucose metabolism, and protein translation induced by impeded mTOR, E2F-related G1/S transcription, ribosomal protein S6 (S6) and, 4E-BP1 activity. This inhibition of mTOR induces a feedback loop involving IGF-1R/INSR activation, which subsequently enables glucose uptake into the cell. IGF1R activation limited the anti-tumor activity of MDL-800 as the PI3K/AKT pathway became hyperactive. Preventing this feedback loop using alpha-specific PI3K inhibitor (BYL719/Alpelisib) resulted in a synergistic anti-tumor effect when MDL-800 and BYL719 were combined. In vivo , the combined treatment of MDL-800 and BYL719 resulted in a prolonged response, with minimal progression observed even 30 days post-initial treatment. Overall, our study identified the molecular mechanisms underlying SIRT6 activation in HNSCC and ESCC. Our findings indicate that SIRT6 activators may have therapeutic potential, either alone or in combination with PI3K inhibition in cancers where SIRT6 is downregulated and serves as a tumor suppressor.