title: TCF7L1 Modulates Colorectal Cancer Growth by Inhibiting Expression of the Tumor-Suppressor Gene EPHB3.
abstract: Dysregulation of the Wnt pathway leading to accumulation of β-catenin (CTNNB1) is a hallmark of colorectal cancer (CRC). Nuclear CTNNB1 acts as a transcriptional coactivator with TCF/LEF transcription factors, promoting expression of a broad set of target genes, some of which promote tumor growth. However, it remains poorly understood how CTNNB1 interacts with different transcription factors in different contexts to promote different outcomes. While some CTNNB1 target genes are oncogenic, others regulate differentiation. Here, we found that TCF7L1, a Wnt pathway repressor, buffers CTNNB1/TCF target gene expression to promote CRC growth. Loss of TCF7L1 impaired growth and colony formation of HCT116 CRC cells and reduced tumor growth in a mouse xenograft model. We identified a group of CTNNB1/TCF target genes that are activated in the absence of TCF7L1, including EPHB3, a marker of Paneth cell differentiation that has also been implicated as a tumor suppressor in CRC. Knockdown of EPHB3 partially restores growth and normal cell cycle progression of TCF7L1-Null cells. These findings suggest that while CTNNB1 accumulation is critical for CRC progression, activation of specific Wnt target genes in certain contexts may in fact inhibit tumor growth.
authors.affiliation: New York University Langone Medical Center, Perlmutter Cancer Center, Department of Stem Cell Biology, 522 1st Ave., Smilow Research Building, Rm 1206 New York, NY, 10016, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Murphy
authors.affiliation: New York University Langone Medical Center, Perlmutter Cancer Center, Department of Stem Cell Biology, 522 1st Ave., Smilow Research Building, Rm 1206 New York, NY, 10016, USA.|University of Houston, Department of Biochemistry and Biology, Science &Research Building 2, 3455 Cullen Blvd #342, Houston, TX 77004, USA.
authors.forename: Sujash S
authors.initials: SS
authors.lastname: Chatterjee
authors.affiliation: New York University, Department of Biology, 1009 Silver Center, 100 Washington Square East, New York, NY, 10003, USA.
authors.forename: Sidharth
authors.initials: S
authors.lastname: Jain
authors.affiliation: New York University, Department of Biology, 1009 Silver Center, 100 Washington Square East, New York, NY, 10003, USA.
authors.forename: Manpreet
authors.initials: M
authors.lastname: Katari
authors.affiliation: New York University Langone Medical Center, Perlmutter Cancer Center, Department of Stem Cell Biology, 522 1st Ave., Smilow Research Building, Rm 1206 New York, NY, 10016, USA.|Genome Institute of Singapore, Cancer Therapeutics and Stratified Oncology, 60 Biopolis Street, #02-01, Genome, 138672, Singapore.
authors.forename: Ramanuj
authors.initials: R
authors.lastname: DasGupta
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D036223:Receptor, EphB3 / Q000235:genetics / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D051176:beta Catenin; D036223:Receptor, EphB3