TGF-beta orchestrates proliferation and migration of cancer cells via KRTAP2-3

Transforming growth factor-beta (TGF-beta) increases migration and metastasis of epithelial cancer cells via induction of epithelial-mesenchymal transition (EMT). TGF-beta also inhibits their proliferation by inducing cell cycle arrest in G1 phase. However, the correlation between these tumour-promoting and tumour-suppressing effects of TGF-beta remains unclear. Here, we showed that TGF-beta conferred higher motility and mesenchymal phenotypes to oral cancer cells residing in G1 phase, suggesting that TGF-beta-dependent growth inhibition and increased migration are correlated. Using single cell RNA sequencing, we identified a unique subset of cancer cells under cell cycle arrest in the G1 phase formed during TGF-beta-induced EMT, distinctive from already known canonical EMT. We also identified keratin-associated protein 2-3 (KRTAP2-3) as a regulator of these dual effects of TGF-beta and showed that KRTAP2-3 expression was correlated with tumour progression and poor prognosis in head and neck cancer patients. Deletion of KRTAP2-3 decreased in vitro migration and in vivo metastasis of oral cancer cells. Our findings revealed that TGF-beta induces KRTAP2-3 expression to orchestrate proliferation and migration, indicating that motile cancer cells arrested in G1 phase can be targeted to suppress metastasis.