A short SOX9 peptide mimics SOX9 tumor suppressor activity and is sufficient to inhibit colon cancer cell growth.

Differently from cytotoxic chemotherapies, targeted therapies do not necessarily drive cancer cells toward death, but reduce cell proliferation, angiogenesis, and/or prevent metastasis without affecting healthy cells. Oncogenic proteins that are hyperactivated and/or overexpressed in cancer cells are prime targets for such therapies. On the other hand, the activity of tumor suppressor proteins is more difficult to harness. Here, we identified a short SOX9 sequence (S9pep) located at the hinge between the HMG DNA-binding domain and the SOX-E central conserved domain that mimics SOX9 tumor-suppressive properties. Doxycycline-induced S9pep expression in DID-1 colorectal cancer cells inhibited the growth potential of these cells, including colorectal cancer stem cells, restored cell-cell contact inhibition, and inhibited the activity of the oncogenic Wnt/beta-catenin signaling pathway. It also significantly decreased tumor growth in BALB/cAnNCrl mice grafted with mouse doxycycline-inducible CT26 colorectal cancer cells in which S9pep was induced by treating them with doxycycline. As the Wnt/beta-catenin signaling pathway is constitutively activated in 80% of colorectal cancer and SOX9-inactivating mutations are present in up to 11% of colorectal cancer, S9pep could be a promising starting point for the development of a peptide-based therapeutic approach to restore a SOX9-like tumor suppressor function in colorectal cancer.