Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML.

Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.

[Mechanism of HOXC6 promoting the progression of prostate cancer by activating the SFRP1/Wnt/ß-catenin signaling pathway].

OBJECTIVE: To study the expression of the Homeobox C6 (HOXC6) gene in the homeobox family in PCa, its effect on the biological behavior of PCa cells and its action mechanism. METHODS: Based on the studies of HOXC6 retrieved from the database of Gene Expression Profiling Interactive Analysis (GEPIA), we analyzed the expression of HOXC6 in PCa and the relationship of its expression level with the survival prognosis of the patients. We detected the expression of the HOXC6 protein in PCa tissues and cells by Western blot, stably interfered with the expression of the HOXC6 gene in human PCa DU145 and PC-3 cells and normal prostatic epithelial RWPE-1 cells using the siRNA plasmid, and determined the effects of HOXC6 on the proliferation, migration and invasiveness of PCa cells by CCK8, plate cloning and scratch healing and Transwell invasion assays. Using the GEPIA database, we analyzed the correlation of the Wnt tumor inhibitory factor-secreted frizzled-related protein 1 (SFRP1) gene with HOXC6, and detected the expressions of HOXC6, SFRP1, Wnt and ß-catenin in PC-3 cells after siRNA-HOXC6 transfection by Western blot. RESULTS: The expression of HOXC6 was dramatically higher in the PCa than in the normal prostate tissue (P< 0.01), and in the PCa cells than in the normal prostatic epithelial cells (P< 0.01). Bioinformatics analysis indicated a lower survival rate of the PCa patients with a high than those with a low HOXC6 expression (P = 0.011). The relative expression of the HOXC6 protein, absorbance value, number of clones formed and number of invaded cells were significantly lower in the siRNA group than in the negative controls (P< 0.05). According to the GEPIA database, highly expressed SFRP1 was associated with a good prognosis of PCa, and the protein expressions of Wnt and ß-catenin were markedly increased while that of SFRP1 decreased in the PCa PC-3 cell line (P< 0.05). The expressions of the Wnt and ß-catenin proteins were decreased and that of SFRP1 increased significantly in the siRNA-HOXC6 transfection group compared with those in the siRNA negative control and PCa PC-3 groups (P< 0.05). CONCLUSION: HOXC6 is highly expressed in PCa tissues and related to the proliferation, migration and invasiveness of PCa cells. HOXC6 promotes the growth of DU145 and PC-3 cells in PCa by inhibiting the SFRP1/Wnt/ß-catenin signaling pathway, and may be a potential target for clinical treatment of PCa.