Cbx4 Governs HIF-1α to Potentiate Angiogenesis of Hepatocellular Carcinoma by Its SUMO E3 Ligase Activity

Li, Jie; Xu, Ying; Long, Xi-Dai; Wang, Wei; Jiao, Huike; Zhu, Manzhou; Yin, Qianqian; Ma, Li; Zhou, Aiwu; Wang, Li‐Shun; Yao, Ming; Xia, Qiang; Chen, Guoqiang

doi:10.1016/j.ccr.2014.03.013

Cited by 48 publications

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“…Wang et al [64] also showed that Cbx4 expression was upregulated in multiple HCC cell lines and clinical samples, and that HCC patients with a high level of cyto-plasmic Cbx4 have a shorter overall and recurrence-free survival. Intriguingly, our further investigations demonstrated that Cbx4 expression is also positively correlated with VEGF expression and microvessel density (MVD) [17]. In line with these clinical observations, overexpression of Cbx4 but not other members of the Cbx family promotes VEGF expression and in vitro angiogenesis in several HCC cell lines under hypoxia.…”

Section: Hif-1 Sumoylation and Cancersupporting

confidence: 66%

“…Ectopic expression of the Cbx4-CDM mutant increases hypoxia-induced VEGF production and the hypoxia-induced tube-forming ability of vascular endothelial cells to a similar degree to wild-type Cbx4. In contrast, no such increases are seen for all three Cbx4-SIM mutants, which maintain the polycomb function but lose SUMO E3 ligase activity [17]. Conversely, the knockdown of HIF-1 or HIF-1 with their specific shRNAs almost completely abolishes hypoxia-induced VEGF expression, supporting the essential role of HIF-1 sumoylation in Cbx4-dependent VEGF expression.…”

Section: Hif-1 Sumoylation and Cancermentioning

confidence: 61%

“…Moreover, orthotopically transplanted SMMC-7721 [17] and MHCC97L cells [65] ectopically expressing Cbx4 and Cbx4-CDM present significantly more lung metastasis nodules than vehicle and Cbx4-SIM1/2-infected tumors. Conversely, the knockdown of endogenous Cbx4 causes SMMC-7721 and MHCC97L cells to produce significantly lower tumor burden than cells transfected with vehicle alone in BALB/c nude mice [17].…”

Section: Hif-1 Sumoylation and Cancermentioning

confidence: 99%

“…HIF-1 can be desumoylated by ectopic SENP1 expression. Under hypoxic conditions, the silencing of Cbx4 by its specific shRNAs inhibits HIF-1 sumoylation in HCC cells [17]. Recent analyses have shown that for Cbx4 two functional SIMs (SIM1 and SIM2, Figure 1A) are prerequisites for its SUMO E3 ligase activity [57,58].…”

Section: Cbx4 and Hif-1 Sumoylationmentioning

confidence: 99%

“…Their transcriptional activities, protein stabilization, protein-protein interactions, and cellular localization are mainly modulated by post-translational modifications such as hydroxylation, ubiquitination, acetylation, phosphorylation and S-nitrosylation [15,16]. Recently, we reported that polycomb chromobox 4 (Cbx4, Figure 1A) governs the transcriptional activity of HIF-1α by enhancing its sumoylation, and hence potentiating angiogenesis of hepatocellular carcinoma (HCC) [17]. Here we review the current understanding of HIF-1 sumoylation, and its effects on protein stabilization and transcriptional activity of HIF-1, as well as its roles in the pathogenesis of cancer.…”

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confidence: 99%

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Sumoylation of hypoxia inducible factor-1α and its significance in cancer

Jiao

et al. 2014

Sci. China Life Sci.

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Hypoxia-inducible factor-1 (HIF-1) is a key heterodimeric transcription factor for the cellular adaptive response to hypoxia, a common feature of the microenvironment in solid tumors. The transcriptional activity, protein stabilization, protein-protein interactions and cellular localization of HIF-1, an oxygen-sensitive subunit of HIF-1, are mainly modulated by various post-translational modifications. Recently, we reported that polycomb chromobox 4 (Cbx4) governs the transcriptional activity of HIF-1α by enhancing its sumoylation at K391 and K477, through which Cbx4 potentiates angiogenesis of hepatocellular carcinoma. This review summarizes the current knowledge of HIF-1 sumoylation and its roles in the pathogenesis of cancer.

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Section: Hif-1 Sumoylation and Cancersupporting

confidence: 66%

Section: Hif-1 Sumoylation and Cancermentioning

confidence: 61%

Section: Hif-1 Sumoylation and Cancermentioning

confidence: 99%

Section: Cbx4 and Hif-1 Sumoylationmentioning

confidence: 99%

mentioning

confidence: 99%

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Sumoylation of hypoxia inducible factor-1α and its significance in cancer

Jiao

et al. 2014

Sci. China Life Sci.

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Blocking Triggering Receptor Expressed on Myeloid Cells‐1‐Positive Tumor‐Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti‐Programmed Cell Death Ligand 1 Resistance in Liver Cancer

et al. 2019

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Tumor‐associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1α induced increased expression of triggering receptor expressed on myeloid cells‐1 (TREM‐1) in TAMs, resulting in immunosuppression. Specifically, TREM‐1‐positive (TREM‐1+) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8+ T cells and induced CD8+ T‐cells apoptosis. Biological and functional assays showed that TREM‐1+ TAMs had higher expression of programmed cell death ligand 1 (PD‐L1) under hypoxic environment. However, TREM‐1+ TAMs could abrogate spontaneous and PD‐L1‐blockade‐mediated antitumor effects in vivo, suggesting that TREM‐1+ TAM‐induced immunosuppression was dependent on a pathway separate from PD‐L1/programmed cell death 1 axis. Moreover, TREM‐1+ TAM‐associated regulatory T cells (Tregs) were crucial for HCC resistance to anti‐PD‐L1 therapy. Mechanistically, TREM‐1+ TAMs elevated chemokine (C‐C motif) ligand 20 expression through the extracellular signal‐regulated kinase/NF‐κβ pathway in response to hypoxia and tumor metabolites leading to CCR6+Foxp3+ Treg accumulation. Blocking the TREM‐1 pathway could significantly inhibit tumor progression, reduce CCR6+Foxp3+ Treg recruitment, and improve the therapeutic efficacy of PD‐L1 blockade. Thus, these data demonstrated that CCR6+Foxp3+ Treg recruitment was crucial for TREM‐1+ TAM‐mediated anti‐PD‐L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion: This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM‐1+ TAMs attracting CCR6+Foxp3+ Tregs, and TREM‐1+ TAMs endowed HCC with anti‐PD‐L1 therapy resistance.

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SIRT1 Regulates N6‐Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2‐Dependent FTO SUMOylation

et al. 2020

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BaCKgRoUND aND aIMS: Hepatocellular carcinoma (HCC) is associated with high malignancy rates. Recently, a known deacetylase silent information regulator 1 (SIRT1) was discovered in HCC, and its presence is positively correlated with malignancy and metastasis. N 6-methyladenosine (m 6 A) is the most prominent modification, but the exact mechanisms on how SIRT1 regulates m 6 A modification to induce hepatocarcinogenesis remain unclear. appRoaCH aND ReSUltS: Here we demonstrate that SIRT1 exerts an oncogenic role by down-regulating fat mass and obesity-associated protein (FTO), which is an m 6 A demethylase. A crucial component of small ubiquitin-related modifiers (SUMOs) E3 ligase, RANBP2, is activated by SIRT1, and it is indispensable for FTO SUMOylation at Lysine (K)-216 site that promotes FTO degradation. Moreover, Guanine nucleotide-binding protein G (o) subunit alpha (GNAO1) is identified as m 6 A downstream targets of FTO and tumor suppressor in HCC, and depletion of FTO by SIRT1 improves m 6 A + GNAO1 and down-regulates its mRNA expression. CoNClUSIoNS: We demonstrate an important mechanism whereby SIRT1 destabilizes FTO, steering the m 6 A + of downstream molecules and subsequent mRNA expression in HCC tumorigenesis. Our findings uncover a target of SIRT1 for therapeutic agents to treat HCC.

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Cbx4 Governs HIF-1α to Potentiate Angiogenesis of Hepatocellular Carcinoma by Its SUMO E3 Ligase Activity

Cited by 48 publications

References 0 publications

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

Blocking Triggering Receptor Expressed on Myeloid Cells‐1‐Positive Tumor‐Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti‐Programmed Cell Death Ligand 1 Resistance in Liver Cancer

SIRT1 Regulates N6‐Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2‐Dependent FTO SUMOylation

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