A Two-Step Model for Colon Adenoma Initiation and Progression Caused by APC Loss

Abstract

Summary Aberrant Wnt/β-catenin signaling following loss of the tumor suppressor adenomatous polyposis coli (APC) is thought to initiate colon adenoma formation. Using zebrafish and human cells, we show that homozygous loss of APC causes failed intestinal cell differentiation, but that this occurs in the absence of nuclear β-catenin and increased intestinal cell proliferation. Therefore, loss of APC is insufficient for causing β-catenin nuclear localization. APC mutation-induced intestinal differentiation defects instead depend on the transcriptional corepressor CtBP1 whereas proliferation defects, and nuclear accumulation of β-catenin, require the additional activation of KRAS. These findings suggest that, following APC loss, CtBP1 contributes to adenoma initiation as a first step, while KRAS activation and β-catenin nuclear localization promotes adenoma progression to carcinomas as a second step. Consistent with this model, human FAP adenomas showed robust upregulation of CtBP1 in the absence of detectable nuclear β-catenin, whereas nuclear β-catenin was detected in carcinomas.

Escape from p21-mediated Oncogene-induced Senescence Leads to Cell Dedifferentiation and Dependence on Anti-apoptotic Bcl-xL and MCL1 Proteins

“…However, other abnormalities are necessary to allow a complete cell transformation. For instance, RAS mutation is an important step in the activation of the ␤-catenin pathway and during carcinoma progression (44). In light of our results and others, we speculate that OIS is probably not completely inactivated following the initial ␤-catenin activation and that this suppressor pathway remains partially functional to restrain cell proliferation in response to secondary mutations.…”

Learning about the functions of NME/NM23: lessons from knockout mice to silencing strategies

“…Other pathways than PTEN probably also hyperactivate Akt upon NME1 silencing, however, since PTEN is not depleted in silenced colon carcinoma cells, implying cell type-specific differences in the response to NME1 silencing. Recent studies implicate a signaling cascade through PI3K, Rac1, and JNK leading to nuclear accumulation of β-catenin and induction of transcription (Wu et al 2008;Phelps et al 2009). The large increase in Rac1-GTP observed upon NME1 silencing suggests that NME1 inhibits GTP loading onto Rac1 (Boissan et al 2010).…”

C-terminus of Hsc70-interacting protein regulates C-terminal binding protein 2 and the expression of its target genes

“…Up-regulation of CtBPs has been reported. Elevated CtBP1 protein is implicated in initiation of human adenoma [11], and CtBP2 protein is highly expressed in breast [12] and ovarian cancers [13]. In addition, high expression of both proteins has been reported in colon cancer [14].…”

“…Adenomatous polyposis coli targets CtBP1 for degradation [11]. CtBPs are phosphorylated by homeodomaininteracting protein kinase-2 (HIPK2) upon ultraviolet (UV) irradiation and subsequently targeted for proteasome-dependent degradation [16].…”