WDR5 positively regulates p53 stability by inhibiting p53 ubiquitination

Abstract

WD40 repeat protein WDR5 is a core component of the Set/MLL histone methyltransferase complex which catalyzes histone H3 Lys4 trimethylation and activates gene transcription in human cells. WDR5 promotes Set/MLL complex assembly and mediates the complex binding to Lys4-dimethylated histone H3 tail. Most earlier studies report that WDR5 exerts profound effects on various cellular and organismal processes mainly through epigenetic regulation of gene transcription. However, the functions of WDR5 in lung cancer remain largely unknown. Here, we report that WDR5 positively regulates p53 stability by inhibiting p53 ubiquitination in human lung cancer A549 cells. Overexpression of WDR5 dramatically increases p53 protein levels and its half-life in A549 cells, while depletion of WDR5 with WDR5-specific siRNAs significantly decreases p53 protein levels. We also observe that WDR5 is required for p53 induction in response to cisplatin treatment. Mechanistically, WDR5 colocalizes with p53 and inhibits p53 ubiquitination, resulting in p53 stabilization. Consequently, overexpression of WDR5 induces G1 phase arrest in A549 cells, and knocking down WDR5 by siRNAs reduces the population at G1 phase. Furthermore, p53 expression levels is at least in part determined by the p53 positive regulator WDR5 in some cancer cells. Taken together, these data suggest that WDR5 is directly involved in p53 signaling pathway. Our studies provide a new insight into WDR5 functions in A549 cells.

p53 Integrates Temporal WDR5 Inputs during Neuroectoderm and Mesoderm Differentiation of Mouse Embryonic Stem Cells

“…Interacts with p53 during ESC Specification Next, we sought to explore the mechanism(s) by which WDR5 regulates p53. We found that Wdr5 extended void did not alter p53 transcripts (Figure 7A) (Sun et al, 2015;Xie et al, 2017). We noticed that ChIP-seq peaks representing WDR5 bound to RP genes were overrepresented (Figures S4E and S7A; data not shown).…”

WDR5 is a prognostic biomarker of brain metastasis from non-small cell lung cancer

“…The scores of positively stained cell percentage were delineated as: score 1 for <25% positive cells; score 2 for 25%-50% positive cells; score 3 for 50%-75% positive cells; score 4 for 75%-100% positive cells. The final score ranged from 0 to 12, and the cut-off was identified by receiver operating characteristic (ROC) curve as previous studies ( 22 , 26 ). Our cohort was separated to WDR5 low and WDR5 high subsets based on the cut-off of IHC score, which was defined as 3.0 in our study.…”

“…In lung cancer, WDR5 is reported to promote proliferation of lung adenocarcinoma by inducing SOX9 expression ( 21 ). In LC cell line A549 cells, WDR5 positively regulates P53 stability and arrests A549 cell cycle in G1 phase ( 22 ), which is conflicting with most studies indicating WDR5 as a tumor-promotor. However, the expression and clinical indications of WDR5 in BM from NSCLC are still unknown.…”

DDX21 Interacts with WDR5 to Promote Colorectal Cancer Cell Proliferation by Activating CDK1 Expression

“…WDR5 can form protein complexes with transcription factors to regulate gene transcription. Recent studies have revealed that WDR5 plays key roles in the tumorigenesis and progression of a variety of cancers, such as breast cancer [27], neuroblastoma [28], pancreatic cancer [29], prostate cancer [30], gastric cancer [31] and non-small cell lung cancer [32,33]. However, similarly, its roles in colon cancer are less understood.…”