TCF4, also known as transcription factor-4, is a transcription factor implicated in the WNT signaling pathway. It plays a crucial role in various biological processes as it forms a complex with β-catenin to activate the transcription of genes involved in cell proliferation [4].

In prostate cancer, TCF4 was found to induce enzalutamide resistance via neuroendocrine differentiation. RNA sequence analysis showed increased TCF4 expression in enzalutamide-resistant LNCaP cells, and inducible TCF4 overexpression led to enzalutamide-resistance in a mouse xenograft model. Small molecule inhibitors of TCF4 partially reversed this resistance [1]. In colorectal cancer, TCF4 enhances hepatic metastasis by regulating tumor-associated macrophage via CCL2/CCR2 signaling. TCF4 deficiency in MC38 cells reduced TAM infiltration and M2 polarization in the metastasis site in a syngeneic mouse model [2]. In osteosarcoma, TCF4 functions as an oncogene. Silencing of circ_0004674, which regulates TCF4 through the miR-140-3p/TCF4 pathway, inhibited cancer cell proliferation, migration, and invasion [3].

In summary, TCF4 is a key transcription factor in the WNT signaling pathway, playing significant roles in cancer-related processes such as drug resistance, metastasis, and cell proliferation. Findings from mouse models, including overexpression and gene-silencing studies, have revealed its functions in prostate, colorectal, and osteosarcoma cancers, providing potential therapeutic targets for these diseases.

References:

1. Lee, Geun Taek, Rosenfeld, Jeffrey A, Kim, Won Tae, Kim, Wun-Jae, Kim, Isaac Yi. 2019. TCF4 induces enzalutamide resistance via neuroendocrine differentiation in prostate cancer. In PloS one, 14, e0213488. doi:10.1371/journal.pone.0213488. https://pubmed.ncbi.nlm.nih.gov/31536510/

2. Tu, Wei, Gong, Jin, Zhou, Zhenzhen, Tian, Dean, Wang, Zhijun. 2021. TCF4 enhances hepatic metastasis of colorectal cancer by regulating tumor-associated macrophage via CCL2/CCR2 signaling. In Cell death & disease, 12, 882. doi:10.1038/s41419-021-04166-w. https://pubmed.ncbi.nlm.nih.gov/34580284/

3. Ma, Yulong, Du, Shaowen, Wang, Shengdong, Shen, Wenxiang, Ye, Kaishan. . Circ_0004674 regulation of glycolysis and proliferation mechanism of osteosarcoma through miR-140-3p/TCF4 pathway. In Journal of biochemical and molecular toxicology, 38, e23846. doi:10.1002/jbt.23846. https://pubmed.ncbi.nlm.nih.gov/39243204/

4. Graham, T A, Ferkey, D M, Mao, F, Kimelman, D, Xu, W. . Tcf4 can specifically recognize beta-catenin using alternative conformations. In Nature structural biology, 8, 1048-52. doi:. https://pubmed.ncbi.nlm.nih.gov/11713475/