DDB2: A Novel Regulator of NF-κB and Breast Tumor Invasion

Abstract

The DNA repair protein damaged DNA-binding 2 (DDB2) has been implicated in promoting cell-cycle progression by regulating gene expression. DDB2 is selectively overexpressed in breast tumor cells that are noninvasive, but not in those that are invasive. We found that its overexpression in invasive human breast tumor cells limited their motility and invasiveness in vitro and blocked their ability to colonize lungs in vivo, defining a new function for DDB2 in malignant progression. DDB2 overexpression attenuated the activity of NF-kB and the expression of its target matrix metalloprotease 9 (MMP9). Mechanistic investigations indicated that DDB2 decreased NF-kB activity by upregulating expression of IkBa by binding the proximal promoter of this gene. This effect was causally linked to invasive capacity. Indeed, knockdown of DDB2-induced IkBa gene expression restored NF-kB activity and MMP9 expression, along with the invasive properties of breast tumor cells overexpressing DDB2. Taken together, our findings enlighten understanding of how breast cancer cells progress to an invasive phenotype and underscore potential clinical interest in DDB2 as a prognostic marker or therapeutic target in this setting. Cancer Res; 73(16); 5040-52. Ó2013 AACR.

DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer

“…Interestingly, a putative DDB2 binding element TCCCCTAA, which is one nucleotide different from the ones found in NFKBIA (15) or NEDD4L (14), is located between the fragments P2 and P3. The available PAM motif in the region around that DDB2-cognate element and CRISPR/Cas9 genome editing technique allowed us to generate two HT-29 cell lines that harbor deletions of 132bp (between P2 and P3) and 416bp (partially overlapping with P2 and P3) (Figs.…”

“…DDB2 associates with the promoter region of its target genes, including SOD2, NFKBIA and NEDD4L (13–15). To study whether DDB2 also associates with the Rnf43 promoter, Chromatin immunoprecipitation (ChIP) assays were conducted in HCT116 cells.…”

“…DDB2 also possesses transcriptional stimulatory activity. It binds to the promoter of the NFKBIA gene to activate its expression and regulate NF-kB activity, and that has been linked to regulation of invasiveness of breast cancer cells (15). That study also identified a DNA-element (TCCCCTTA) specifically recognized by DDB2 in the NFKBIA gene (14).…”

Shikonin as an inhibitor of the LPS-induced epithelial-to-mesenchymal transition in human breast cancer cells

“…NF-κB is a structurally conserved family of dimeric transcription factors that plays pivotal roles in maintaining an invasive phenotype as well as promoting carcinogenesis (30). It also plays a central role in EMT through direct activation of the transcription of Snail, which has been established as a critical mediator of EMT (31).…”

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].…”