DDB2 Suppresses Epithelial-to-Mesenchymal Transition in Colon Cancer

Abstract

Colon cancer is one of the deadliest cancers worldwide because of its metastasis to other essential organs. Metastasis of colon cancer involves a complex set of events, including epithelial to mesenchymal transition (EMT) that increases invasiveness of the tumor cells. Here we show that the xeroderma pigmentosum group E (XPE) gene product DDB2 is down-regulated in high-grade colon cancers, and it plays a dominant role in the suppression of EMT of the colon cancer cells. Depletion of DDB2 promotes mesenchymal phenotype, whereas expression of DDB2 promotes epithelial phenotype. DDB2 constitutively represses genes that are the key activators of EMT, indicating that DDB2 is a master regulator of EMT of the colon cancer cells. Moreover, we observed evidence that DDB2 functions as a barrier for EMT induced by hypoxia and TGF-β. Also, we provide evidence that DDB2 inhibits metastasis of colon cancer. The results presented here identify a transcriptional regulatory pathway of DDB2 that is directly linked to the mechanisms that suppress metastasis of colon cancer.

DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer

“…Two distinct siRNAs targeting different regions of the gene were used to eliminate off-target effect. HCT116 cells stably expressing shRNA targeting DDB2 were described before (17). HCT116 cells stably expressing FLAG-HA-tagged DDB2 were established using a retroviral vector (16).…”

“…The protein level of DDB2 decreases in metastatic colon cancer, and that coincides also with loss of cell surface E-cadherin expression (17). Depletion of DDB2 in an orthotopic mouse model for colon cancer causes a strong increase in metastasis of the colon cancer cells to the liver.…”

“…Depletion of DDB2 in an orthotopic mouse model for colon cancer causes a strong increase in metastasis of the colon cancer cells to the liver. Reciprocally, expression of DDB2 suppresses metastatic potential of colon cancer cells harboring mutations in the Wnt-pathway (17). The metastasis suppressor function of DDB2, at least partly, correlates with suppression of epithelial to mesenchymal (EMT)-like changes of the colon cancer cells (17).…”

“…Reciprocally, expression of DDB2 suppresses metastatic potential of colon cancer cells harboring mutations in the Wnt-pathway (17). The metastasis suppressor function of DDB2, at least partly, correlates with suppression of epithelial to mesenchymal (EMT)-like changes of the colon cancer cells (17). For example, expression of DDB2 in SW620 cells, mesenchymal type, changes the morphology to epithelial type.…”

The 5′-UTR of DDB2 harbors an IRES element and upregulates translation during stress conditions

“…Besides DDB2 could promote cellular apoptosis through subduing the levels of Bcl-2 [25,26] and p21 in cells harboring irreparable DNA damage [21,27]. DDB2 could also inhibit colon neoplasm metastasis [28] and limit the invasiveness and motility of invasive human breast tumor cells through controlling NF-κB activity [29], as well as mediating senescence [29]. Furthermore, new studies found that DDB2 overexpression caused a reduction of the cancer stem cells population related to repress the oncogenicity of ovarian cancer cells, nevertheless the knockdown of DDB2 caused an expansion of the cancer stem cells population [30].…”