FOXK transcription factors: Regulation and critical role in cancer

Liu, Ying; Ding, Wei; Hu, Ge; Ponnusamy, Murugavel; Wang, Qiong; Hao, Xiaodan; Wu, Wei; Zhang, Yuan; Yu, Wanpeng; Ao, Xiang; Wang, Jianxun

doi:10.1016/j.canlet.2019.05.030

Cited by 45 publications

(36 citation statements)

References 144 publications

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“…Previous studies have identified a crucial role of FOXK1 in cancers [33][34][35]. To explore whether HUMT exerted its function through FOXK1-mediated cell proliferation and vascular endothelial growth factor (VEGFC) signaling, which was a previously reported key lymphangiogenesis pathway [36,37], we analyzed the effect of HUMT-KO by western blot.…”

Section: Foxk1 Is Crucial To Humt-mediated Cell Proliferation Metastmentioning

confidence: 99%

Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer

et al. 2020

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Background: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with highly invasive ability and metastatic nature to the lymph nodes. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis and progression. However, their roles in TNBC lymph node metastasis remains rarely studied. Methods: The expression of lncRNA highly upregulated in metastatic TNBC (HUMT) in cell lines and tissues was detected by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). RNA immunoprecipitation (RIP) and RNA pulldown were used to verify the interaction between lncRNA and protein. Chromatin immunoprecipitation (CHIP) and dCas9-gRNA-guided chromatin immunoprecipitation (dCas9-CHIP) were conducted to identify the specific binding site of HUMT-YBX1 complex. Western blot was used to detect the downstream of HUMT. Results: HUMT was significantly upregulated in lymph node invasive cells and predicted poorer clinical prognosis. Functional study indicated that HUMT promoted lymphangiogenesis and lymph node metastasis. Bioinformatic analysis and qRT-PCR showed that the high expression of HUMT was correlated with the hypomethylation status of its promoter region. Further, HUMT recruited Y-box binding protein 1 (YBX1) to form a novel transcription complex and activated the expression of forkhead box k1 (FOXK1), thus enhancing the expression of vascular endothelial growth factor C (VEGFC). The therapeutic value was further validated in patient-derived xenograft (PDX) models, and a combined marker panel exhibited a better prognostic value for TNBC in receiver operating characteristic (ROC) analysis. Conclusions: Our study identified a novel TNBC lymph node metastasis-associated lncRNA, which promoted TNBC progression and indicated a novel biomarker and potential therapeutic target for TNBC lymph node metastasis.

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Section: Foxk1 Is Crucial To Humt-mediated Cell Proliferation Metastmentioning

confidence: 99%

Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer

et al. 2020

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“…Purification of proteins associated with FOXK1 and FOXK2 also shows robust enrichment of PR-DUB, strongly supporting that they are integral components of PR-DUBs (Ji et al 2014;Okino et al 2015). FOXK1 and FOXK2 also copurify with other chromatin modifying complexes (Liu et al 2019;Nestal de Moraes et al 2019), suggesting that these TFs target a variety of enzymatic activities to chromatin to regulate transcription. Although other genome-wide studies have found strong enrichment of ETS motifs for BAP1 and ASXL1 binding regions (Abdel-Wahab et al 2012;Dey et al 2012), our analysis of BAP1 binding regions showed that the strongest enrichment of the consensus motif for members was the FOX family.…”

Section: Discussionmentioning

confidence: 74%

PR-DUB maintains the expression of critical genes through FOXK1/2- and ASXL1/2/3-dependent recruitment to chromatin and H2AK119ub1 deubiquitination

et al. 2020

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Polycomb group proteins are important for maintaining gene expression patterns and cell identity in metazoans. The mammalian Polycomb repressive deubiquitinase (PR-DUB) complexes catalyze removal of monoubiquitination on lysine 119 of histone H2A (H2AK119ub1) through a multiprotein core comprised of BAP1, HCFC1, FOXK1/2, and OGT in combination with either of ASXL1, 2, or 3. Mutations in PR-DUB components are frequent in cancer. However, mechanistic understanding of PR-DUB function in gene regulation is limited. Here, we show that BAP1 is dependent on the ASXL proteins and FOXK1/2 in facilitating gene activation across the genome. Although PR-DUB was previously shown to cooperate with PRC2, we observed minimal overlap and functional interaction between BAP1 and PRC2 in embryonic stem cells. Collectively, these results demonstrate that PR-DUB, by counteracting accumulation of H2AK119ub1, maintains chromatin in an optimal configuration ensuring expression of genes important for general functions such as cell metabolism and homeostasis.

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“…Currently, the main treatments for cancer are surgery, chemotherapy and radiation therapy, which are designed to eliminate tumor cells by directly removing or killing them 2 - 4 . With extensive research based on tumor biology, various genes and proteins have demonstrated potential inhibitory effects on tumor growth and proliferation, such as noncoding RNA, certain transcription factors and apoptotic pathway activators associated with tumor growth 5 - 8 . Moreover, a new therapeutic strategy, which eliminates tumor cells by enhancing the immunity of patients, called immunotherapy, is becoming a popular therapeutic method for mono- or polytherapy of malignant tumors 9 , 10 .…”

Section: Introductionmentioning

confidence: 99%

Targeting phosphatidylserine for Cancer therapy: prospects and challenges

Chang

Xiao

et al. 2020

Theranostics

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Cancer is a leading cause of mortality and morbidity worldwide. Despite major improvements in current therapeutic methods, ideal therapeutic strategies for improved tumor elimination are still lacking. Recently, immunotherapy has attracted much attention, and many immune-active agents have been approved for clinical use alone or in combination with other cancer drugs. However, some patients have a poor response to these agents. New agents and strategies are needed to overcome such deficiencies. Phosphatidylserine (PS) is an essential component of bilayer cell membranes and is normally present in the inner leaflet. In the physiological state, PS exposure on the external leaflet not only acts as an engulfment signal for phagocytosis in apoptotic cells but also participates in blood coagulation, myoblast fusion and immune regulation in nonapoptotic cells. In the tumor microenvironment, PS exposure is significantly increased on the surface of tumor cells or tumor cell-derived microvesicles, which have innate immunosuppressive properties and facilitate tumor growth and metastasis. To date, agents targeting PS have been developed, some of which are under investigation in clinical trials as combination drugs for various cancers. However, controversial results are emerging in laboratory research as well as in clinical trials, and the efficiency of PS-targeting agents remains uncertain. In this review, we summarize recent progress in our understanding of the physiological and pathological roles of PS, with a focus on immune suppressive features. In addition, we discuss current drug developments that are based on PS-targeting strategies in both experimental and clinical studies. We hope to provide a future research direction for the development of new agents for cancer therapy.

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FOXK transcription factors: Regulation and critical role in cancer

Cited by 45 publications

References 144 publications

Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer

Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer

PR-DUB maintains the expression of critical genes through FOXK1/2- and ASXL1/2/3-dependent recruitment to chromatin and H2AK119ub1 deubiquitination

Targeting phosphatidylserine for Cancer therapy: prospects and challenges

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