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

The proliferation and migration of cancer cells are regulated by stimuli from the tumour microenvironment during tumour progression and metastasis. While transforming growth factor-β (TGF-β) increases migration and metastasis of various types of epithelial cancer cells via induction of epithelial-mesenchymal transition (EMT), it also inhibits their proliferation by inducing cell cycle arrest in the G1 phase. However, the correlation between the tumour promoting and suppressing effects of TGF-β remains elusive because of the lack of analysis at the single-cell level. Here, we showed that TGF-β conferred higher motility and mesenchymal phenotypes to oral cancer cells residing in the G1 phase, suggesting a correlation between TGF-β-dependent cell cycle arrest and increased cell migration. We identified keratin-associated protein 2-3 (KRTAP2-3) as a regulator of these dual effects of TGF-β and showed that the expression of KRTAP2-3 was associated with TGF-β-induced cell cycle arrest and increased migration and correlated with poor prognosis in patients with head and neck cancer. Deletion of the KRTAP2-3 gene decreased in vitro migration and in vivo metastasis of oral cancer cells via induction of mesenchymal-epithelial transition. KRTAP2-3 also induced the expression of the zinc finger BED domain-containing protein 2 and ectodermal-neural cortex 1, which suppressed proliferation and increased migration of oral cancer cells, respectively. The present findings revealed the mechanisms by which TGF-β orchestrates proliferation and migration of cancer cells by inducing the expression of KRTAP2-3 and highlighted the importance of targeting motile cancer cells under cell cycle arrest in the G1 phase to suppress metastasis. Identification of marker genes for KRTAP2-3 induced gene The effect of expression on KRTAP2-3 in oral cancer was examined. KRTAP2-3 was expressed or knocked out in cancer cells.