A dynamic exchange of TCF3 and TCF4 transcription factors controls MYC expression in colorectal cancer cells

Abstract

Deregulated Wnt/b-catenin signaling promotes colorectal cancer (CRC) by activating expression of the c-MYC protooncogene (MYC). In the nucleus, the b-catenin transcriptional co-activator binds T-cell factor (TCF) transcription factors, and together TCF/b-catenin complexes activate MYC expression through Wnt responsive DNA regulatory elements (WREs). The MYC 3' WRE maps 1.4-kb downstream from the MYC transcription stop site and binds TCF4/b-catenin transcription complexes to activate MYC. However, the underlying mechanisms for how this element operates are not fully understood. Here, we report that the TCF family member, TCF3, plays an important role in regulating MYC expression in CRCs. We demonstrate that TCF3 binds the MYC 3 0 WRE to repress MYC. When TCF3 is depleted using shRNAs, the MYC 3 0 WRE is more available to bind TCF4/b-catenin complexes. Stimulating downstream Wnt/b-catenin signaling by inhibiting GSK3b causes an exchange of TCF3 with TCF4/b-catenin complexes to activate MYC. Finally, this transcription factor switch at the MYC 3 0 WRE controls MYC expression as quiescent cells re-enter the cell cycle and progress to S phase. These results indicate that a dynamic interplay of TCF transcription factors governs MYC gene expression in CRCs.

The increased expression of TCF3 is correlated with poor prognosis in Chinese patients with nasopharyngeal carcinoma

“…In the present study, we found that TCF3 expression was significantly increased in NPC tissues compared to non‐tumourous nasopharyngeal tissues, which suggests that TCF3 is also involved in NPC carcinogenesis. It has been reported that TCF3 overexpression serves as a prognostic marker for judging the survival of patients in several types of human cancers . In this regard, we analysed the relationship between TCF3 staining and the clinicopathological characteristics of the 117 patients with NPC and found a significant correlation between TCF3 expression and clinical stage, locoregional recurrence and distant metastasis.…”

“…TCF3 plays important roles in embryonic development and regulates the identity and function of epidermal and embryonic stem cells by promoting either stem cell self‐renewal or differentiation depending on the cellular context . Recent studies have demonstrated that TCF3 expression was also closely related to cancer development and progression in several human tumours . However, the role of TCF3 in NPC was not previously addressed.…”

“…Overexpression of TCF3 in the epidermis blocks terminal differentiation and maintains cells in an undifferentiated state . Emerging evidence indicates that TCF3 plays an important role in the pathogenesis of several types of human cancers . Additionally, the fusion of TCF3 with PBX1 and HLF resulting from abnormal chromosomal translocation in paediatric B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL) is typically associated with prognosis and survival probability of BCP‐ALL patients .…”

“…14,15 Emerging evidence indicates that TCF3 plays an important role in the pathogenesis of several types of human cancers. [16][17][18][19] Additionally, the fusion of TCF3 with PBX1 and HLF resulting from abnormal chromosomal translocation in paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is typically associated with prognosis and survival probability of BCP-ALL patients. 20,21 However, the expression patterns and clinical significance of TCF3 in NPC have not been reported.…”

Modeling Gene Regulation in Liver Hepatocellular Carcinoma with Random Forests

“…Similarly, the next ranked regulator TCF3 has been found to regulate breast cancer cell differentiation and tumorigenicity [17]. Additionally, previous literature has revealed that TCF3 and TCF4 are overexpressed in rectal cancer and they control MYC expression in colorectal cells [18]. A previous study identified ZEB1 as a key promoter of metastasis in pancreatic and colorectal cancer cells [19].…”