Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11

The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network

“…Although it is well established that ZEB1 downregulates miRs by silencing the promoters of the miRs themselves or the expression of transcription factors that drive miR expression (4,11,12), the results of the present study show that ZEB1 can inactivate miRs by upregulating ceRNAs. Furthermore, they build on a growing body of evidence that miRs are key mediators of EMT-TFs.…”

“…Thus, ZEB1 upregulated ITGA1 through ARNT. ZEB1 silences miRs that target key drivers of EMT and metastasis (5,11,12). To determine whether ITGA1 is a target of ZEB1-silenced miRs, we used a prediction algorithm (www.targetscan.…”

“…org) to query the ITGA1 3′-UTR. Binding sites for multiple miRs were identified, including sites for miR-148a, which is silenced by ZEB1 (12). In reporter assays, ITGA1 3′-UTR activity was suppressed by cotransfection of miR-148a or miR-181b ( Figure 4J), and a mutation in the miR-148a-binding site reversed the suppression ( Figure 4J).…”

“…For example, mutual antagonism between the transcription factors and miRs (e.g., ZEB1 and miR-200, SNAIL, and miR-34a) regulates tumor cells' ability to shift reversibly between epithelial and mesenchymal states (3). Additionally, ZEB1 silences the expression of miRs that suppress tumor cell stemness by targeting the stem cell factors SOX2 and KLF4 (e.g., miR-203 and miR-183); that inhibit tumor cell motility by targeting genes that promote the remodeling of actin-based cytoskeletal structures (e.g., miR-34a); and that block vesicle trafficking toward the leading edge of the cell by targeting a Golgi scaffolding protein that promotes the formation of a compact, polarized Golgi organelle (e.g., miR-148a, miR-206, and miR-200) (4,11,12). Additional studies are warranted to determine the degree to which ceRNA networks extend the prometastatic activities of EMT-TFs.…”

“…In breast and lung adenocarcinomas, high ZEB1 expression levels confer tumor-initiating and metastatic activities and are correlated with a poor prognosis (10). ZEB1 downregulates the expression of epithelial polarity genes and microRNAs (miRs; e.g., miR-34a, miR-148a, and miR-200 family members) that promote epithelial differentiation and inhibit tumor initiation and metastasis by regulating actin cytoskeletal remodeling, Golgi compaction, and polarized vesicle trafficking (4,11,12). Thus, miRs are critical downstream effectors of EMT-TFs.…”