Loss of the p53/p63 Regulated Desmosomal Protein Perp Promotes Tumorigenesis

Abstract

Dysregulated cell–cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell–cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell–cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer.

Suppression of Hepatocyte Proliferation by Hepatocyte Nuclear Factor 4α in Adult Mice

“…The regulation of Perp expression by HNF4␣ is consistent with the broad number of cell adhesion-related genes previously identified as HNF4␣ targets, including E-cadherin, claudins 1 and 3, and desmocollin 2 (11). Disruption of Perp promoted UVB-induced squamous cell carcinoma that was attributed to loss of PERP apoptotic functions as well as its desmosomal role (45). The cumulative effect of the loss of several apoptosis genes in Hnf4a F/F;AlbERT2cre knock-out mice may shift the steady-state equilibrium between apoptosis and proliferation.…”

Desmosome assembly, homeostasis, and desmosomal disease

“…165 Furthermore, reexpression of Dsp in cells with an epigenetic inactivation of the Dsp gene exhibited an increased sensitivity to apoptosis by the upregulation of Pg and the concomitant inhibition of β-catenin -TCF/ LEF-dependent transcription. 166 Abnormal proliferative signaling of cancer cells may also be partially controlled by desmosomes via their accessory components (Figure 2), including tyrosine kinases, which are frequently upregulated in cancer. Keratinocytes from Pg-null mice exhibit an increased Src activity correlating with enhanced cell motility.…”

Desmosomal Cadherins in Basal Cell Carcinomas

“…Beaudry et al noted that probably desmosome loss does not promote tumorigenesis via a general trans-differentiation mechanism, but rather via more specific manner related to changes caused by complete desmosome-deficiency (Beaudry et al, 2010). However, studies about expression of desmosome components during human cancer progression have generated conflicting results (Beaudry et al, 2010).…”

“…Beaudry et al noted that probably desmosome loss does not promote tumorigenesis via a general trans-differentiation mechanism, but rather via more specific manner related to changes caused by complete desmosome-deficiency (Beaudry et al, 2010). However, studies about expression of desmosome components during human cancer progression have generated conflicting results (Beaudry et al, 2010). Thus, further genetic studies with animal models, such as knockout mice, to evaluate the functional consequence of desmosome alternation for tumorigenesis are necessary (Beaudry et al, 2010).…”

“…However, studies about expression of desmosome components during human cancer progression have generated conflicting results (Beaudry et al, 2010). Thus, further genetic studies with animal models, such as knockout mice, to evaluate the functional consequence of desmosome alternation for tumorigenesis are necessary (Beaudry et al, 2010). Teh et al found that downregulation of desmosomal components, particularly the DCs, precedes malignancy and is associated with desmosomal dysfunction (Teh et al, 2011).…”