| 1 | HSF1 facilitates the multistep process of lymphatic metastasis in bladder cancer via a novel PRMT5-WDR5-dependent transcriptional program显示文摘Background:Lymphatic metastasis has been associated with poor prognosis in bladder cancer patients with limited therapeutic options.Emerging evidence shows that heat shock factor 1(HSF1)drives diversified transcriptome to promote tumor growth and serves as a promising therapeutic target.However,the roles of HSF1 in lymphatic metastasis remain largely unknown.Herein,we aimed to illustrate the clinical roles and mechanisms of HSF1 in the lymphatic metastasis of bladder cancer and explore its therapeutic potential.Methods:We screened the most relevant gene to lymphatic metastasis among overexpressed heat shock factors(HSFs)and heat shock proteins(HSPs),and analyzed its clinical relevance in three cohorts.Functional in vitro and in vivo assays were performed in HSF1-silenced and-regained models.We also used Coimmunoprecipitation to identify the binding proteins of HSF1 and chromatin immunoprecipitation and dual-luciferase reporter assays to investigate the transcriptional program directed by HSF1.The pharmacological inhibitor of HSF1,KRIBB11,was evaluated in popliteal lymph node metastasis models and patientderived xenograft models of bladder cancer.Results:HSF1 expression was positively associated with lymphatic metastasis status,tumor stage,advanced grade,and poor prognosis of bladder cancer.Importantly,HSF1 enhanced the epithelial-mesenchymal transition(EMT)of cancer cells in primary tumor to initiate metastasis,proliferation of cancer cells in lymph nodes,and macrophages infiltration to facilitate multistep lymphatic metastasis.Mechanistically,HSF1 interacted with protein arginine methyltransferase 5(PRMT5)and jointly induced the monomethylation of histone H3 at arginine 2(H3R2me1)and symmetric dimethylation of histone H3 at arginine 2(H3R2me2s).This recruited the WD repeat domain 5(WDR5)/mixed-lineage leukemia(MLL)complex to increase the trimethylation of histone H3 at lysine 4(H3K4me3);resulting in upregulation of lymphoid enhancer-binding factor 1(LEF1),matrix metallopeptidase 9(MMP9),C-C motif chemokine ligand 20(CCL20),and E2F transcription factor 2(E2F2).Application of KRIBB11 significantly inhibited the lymphatic metastasis of bladder cancer with no significant toxicity.Conclusion:Our findings reveal a novel transcriptional program directed by the HSF1-PRMT5-WDR5 axis during the multistep process of lymphatic metastasis in bladder cancer.Targeting HSF1 could be a multipotent and promising therapeutic strategy for bladder cancer patients with lymphatic metastasis. | Ming Huang Wen Dong Ruihui Xie Jilin Wu Qiao Su Wuguo Li Kai Yao Yuelong Chen Qianghua Zhou Qiang Zhang Wenwen Li Liang Cheng Shengmeng Peng Siting Chen Jian Huang Xu Chen Tianxin Lin | 2022 | Cancer Communications2022，42，5： | 2 |
| 2 | Suppressed mitochondrial respiration via NOX5-mediated redox imbalance contributes to the antitumor activity of anlotinib in oral squamous cell carcinoma显示文摘Anlotinib,a novel multitarget tyrosine kinase inhibitor,has shown promising results in the management of various carcinomas.This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma(OSCC)and the underlying molecular mechanism.A retrospective clinical study revealed that anlotinib improved the median progression-free survival(m PFS)and median overall survival(m OS)of patients with recurrent and metastatic(R/M)OSCC,respectively.Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patientderived xenograft models.Mechanistically,RNA-sequencing identified that oxidative stress,oxidative phosphorylation and AKT/m TOR signaling were involved in anlotinib-treated OSCC cells.Anlotinib upregulated NADPH oxidase 5(NOX5)expression,elevated reactive oxygen species(ROS)production,impaired mitochondrial respiration,and promoted apoptosis.Moreover,anlotinb also inhibited phosphoAkt(p-AKT)expression and elevated p-e IF2αexpression in OSCC cells.NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells.Collectively,we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC.The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/e IF2αpathway. | Zhexun Huang Qiao Su Wuguo Li Hui Ren Huiqiang Huang Anxun Wang | 2021 | Journal of Genetics and Genomics2021，48，7： | 1 |
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