PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407

Abstract

Colorectal cancer (CRC) is the third most common cause of cancer deaths, and has a high rate of liver and lung metastasis. Unfortunately, distant metastasis is the main barrier for advanced CRC therapy and leads to a very low survival rate. In this study, we identified WDR5, a vital factor that regulates vertebrate development and cell self-renewal and reprogramming, as a novel prognostic marker and therapeutic target for CRC patients. We demonstrate that WDR5 is upregulated in CRC tissues and promotes CRC metastasis both in vitro and in vivo. In an effort to investigate the impact of WDR5 on CRC cell fate, we treated CRC cells with growth factor and inhibitor. We report that WDR5 is a novel factor in the metastasis of CRC by triggering epithelial–mesenchymal transition (EMT) process in response to the PI3K/AKT signaling pathway. Moreover, WDR5 shows a direct binding to the ZNF407 promoter on regulating cellular EMT process, leading to CRC metastasis. Hence, our findings strongly position WDR5 as a valuable marker for CRC, and inhibiting WDR5 or the associated signaling pathways may be an effective strategy for the future development of anti-CRC therapy.

Overexpression of WD repeat domain 5 associates with aggressive clinicopathological features and unfavorable prognosis in head neck squamous cell carcinoma

“…This is in agreement with previous studies, in which they reported that WDR5 was critically involved in hypoxia‐induced EMT and metastasis by abolishing mesenchymal gene expression in Fadu cells . In addition, WDR5 promoted EMT and metastatic behavior of colorectal cell in vitro and metastasis in xenograft mouse model by enhancing cell motility via directly regulating ZNF407 . Complementary, our findings also reveal that WDR5 overexpression tend to positively associate with cervical lymph node metastasis, although statistical significance was not achieved.…”

“…Accumulating evidence has suggested that WDR5 functions as a putative oncogene by promoting cell proliferation, EMT, metastasis as well as chemoresistance in human cancer . Consistent with the pro‐proliferative roles of WDR5 in bladder, breast, and prostate cancer, our findings revealed that WDR5 depletion significantly inhibited cell proliferation, colony formation and cell cycle arrest in HNSCC cells.…”

“…In colorectal cancer, high WDR5 expression significantly correlated with TNM stage, lymph node status, and distant metastasis. In addition, patients with high WDR5‐expression signature had shorter overall survival and reduced progression‐free survival . Our data mining and interrogation from TCGA‐HNSCC database failed to reveal positive associations between WDR5 mRNA level and pathological grades, clinical stages as well as overall survival.…”

“…Aberrant overexpression of WDR5 has been found in multiple human malignancies such as bladder, pancreatic, breast cancer, and leukemia. Its overexpression usually correlated with cancer aggressiveness and unfavorable prognosis in these cancers . Moreover, interactions between WDR5 and MYC, HDAC3 or histone H3 threonine 11 phosphorylation (H3T11P) are essential for hypoxia‐induced EMT, MYC‐driven carcinogenesis as well as androgen‐dependent cell proliferation, respectively .…”

High COX‐2 expression in cancer‐associated fibiroblasts contributes to poor survival and promotes migration and invasiveness in nasopharyngeal carcinoma

“…Western blot was performed as previously described . CAF derived from patients with NPC and NPC cells treated with CM were lysed in radioimmunoprecipitation assay buffer containing protease inhibitor cocktail and phosphatase inhibitor cocktails (Roche, Basel, Switzerland) on ice, and the protein levels were quantified by using BCA protein assay kit (Dingguo Biotech Co., Beijing, China), according to the manufacturer's instruction.…”