Cytoplasm-nucleus shuttling of TET2: an intrinsic brake in colorectal cancer progression.

Colorectal Cancer (CRC) progression is a complex and dynamic process closely linked to TET2-mediated DNA demethylation. Distinct from our previous study on TET2 nuclear loss, which can be observed in the whole tumor progression process, the nuclear increase of TET2 was only observed in tumors at the beginning of metastasis. In addition, cells with nuclear TET2 were located at the bottom of the mucosa, which is the invasion front of CRC. All of these results suggested crucial roles of TET2 nuclear increase during tumor progression. Mechanistically, epithelial-mesenchymal transition (EMT) and the activation of the WNT pathway, which is normally recognized as tumor promotion events, were shown to correlate with the cytoplasm-nucleus shuttling of TET2, which is associated with tumor suppression. Nuclear TET2, in turn, mitigated further EMT and WNT activation, suggesting a negative feedback loop between TET2 and the EMT/WNT pathway. Such a negative feedback loop was further supported by single-cell RNA sequencing (scRNA-seq) analysis of both the CRC progression models and the clinical CRC samples. Together, these findings indicate that the tumor inhibition role of EMT/WNT pathway and TET2 is an intrinsic brake on cancer progression, which represents a potential therapeutic target for CRC.