Dissecting the roles and clinical potential of YY1 in the tumor microenvironment

Li, MengNa; Wei, Jianxia; Xue, Changning; Zhou, Xiangting; Chen, ShiPeng; Zheng, Lemei; Duan, Yumei; Deng, HongYu; Wang, Xiong; Tang, FaQing; Li, Guiyuan; Zhou, Ming

doi:10.3389/fonc.2023.1122110

Cited by 17 publications

(10 citation statements)

References 135 publications

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“…Upon conducting a Venn analysis on the predicted VDBP transcription factors from the Cistrome database, the VDR interacting proteins identified by MS, and the VDR interacting proteins in the FPClass database, the presence of Yin-Yang 1 (YY1) was found (Figure 6 B). YY1, belonging to the GLI-Kruppel family of transcription factors, acts as a DNA binding protein and is involved in numerous biological processes, including cell growth, embryonic development, transcriptional regulation, and tumorigenesis 31 , 32 . The interaction between the VDR and YY1 was validated through Co-IP and PLA experiments, and an increase in their interaction was observed with an increase in VD dosage (Figure 6 C-D).…”

Section: Resultsmentioning

confidence: 99%

Vitamin D binding protein (VDBP) hijacks twist1 to inhibit vasculogenic mimicry in hepatocellular carcinoma

Qin,

Zhang,

et al. 2024

Theranostics

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Rationale: Vitamin D (VD) has been suggested to have antitumor effects, however, research on the role of its transporter vitamin D-binding protein (VDBP, gene name as GC ) in tumors is limited. In this study, we demonstrated the mechanism underlying the inhibition of vasculogenic mimicry (VM) by VDBP in hepatocellular carcinoma (HCC) and proposed an anti-tumor strategy of combining anti-PD-1 therapy with VD. Methods: Three-dimensional cell culture models and mice with hepatocyte-specific GC deletion were utilized to study the correlation between VDBP expression and VM. A patient-derived tumor xenograft (PDX) model was further applied to validate the therapeutic efficacy of VD in combination with an anti-PD-1 drug. Results: The study revealed that VDBP expression is negatively correlated with VM in HCC patients and elevated VDBP expression is associated with a favorable prognosis. The mechanism studies suggested VDBP hindered the binding of Twist1 on the promoter of VE-cadherin by interacting with its helix-loop-helix DNA binding domain, ultimately leading to the inhibition of VM. Furthermore, VD facilitated the translocation of the vitamin D receptor (VDR) into the nucleus where VDR interacts with Yin Yang 1 (YY1), leading to the transcriptional activation of VDBP. We further demonstrated that the combination of VD and anti-PD-1 led to an improvement in the anti-tumor efficacy of an anti-PD-1 drug. Conclusion: Collectively, we identified VDBP as an important prognostic biomarker in HCC patients and uncovered it as a therapeutic target for enhancing the efficacy of immune therapy.

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Section: Resultsmentioning

confidence: 99%

Vitamin D binding protein (VDBP) hijacks twist1 to inhibit vasculogenic mimicry in hepatocellular carcinoma

Qin,

Zhang,

et al. 2024

Theranostics

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“…Cyclooxygenase 2 (COX-2), an enzyme associated with inflammatory responses, is another mediator in the regulation of PD-L1 by YY1. YY1 binds directly to the COX-2 promoter, positively regulating its expression in inflammatory contexts [ 155 , 156 ]. In vitro, inhibition of COX-2 was shown to downregulate PD-L1 expression in melanoma cells [ 157 ].…”

Section: Regulation Of Pd-l1 By Yy1mentioning

confidence: 99%

“…There is significant current evidence regarding the impact of YY1 regulation of PD-L1 in several cancers. Multiple studies have implicated the YY1/PD-L1 axis in immune escape in melanoma, NSCLC, liver cancer, and lymphoma [ 47 , 156 ]. It has been determined that YY1 is an important regulator of PD-L1 during T-cell exhaustion and promotes immune escape in prostate cancer [ 115 , 208 , 212 ].…”

Section: Overall Perspectives and Future Directionsmentioning

confidence: 99%

“…It has been determined that YY1 is an important regulator of PD-L1 during T-cell exhaustion and promotes immune escape in prostate cancer [ 115 , 208 , 212 ]. YY1 is also implicated in the resistance of immune checkpoint therapies, and it can disrupt immunotherapy treatments through disruption of the PD-1/PD-L1 axis [ 156 , 213 ]. Additionally, YY1 is linked to tumor immune evasion through the upregulation of PD-L1 through regulation of the p53/miR-34/PD-L1 pathway [ 187 ].…”

Section: Overall Perspectives and Future Directionsmentioning

confidence: 99%

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Regulation of PD-L1 Expression by YY1 in Cancer: Therapeutic Efficacy of Targeting YY1

Dillen,

Bui,

Jung

et al. 2024

Cancers

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During the last decade, we have witnessed several milestones in the treatment of various resistant cancers including immunotherapeutic strategies that have proven to be superior to conventional treatment options, such as chemotherapy and radiation. This approach utilizes the host’s immune response, which is triggered by cancer cells expressing tumor-associated antigens or neoantigens. The responsive immune cytotoxic CD8+ T cells specifically target and kill tumor cells, leading to tumor regression and prolongation of survival in some cancers; however, some cancers may exhibit resistance due to the inactivation of anti-tumor CD8+ T cells. One mechanism by which the anti-tumor CD8+ T cells become dysfunctional is through the activation of the inhibitory receptor programmed death-1 (PD-1) by the corresponding tumor cells (or other cells in the tumor microenvironment (TME)) that express the programmed death ligand-1 (PD-L1). Hence, blocking the PD-1/PD-L1 interaction via specific monoclonal antibodies (mAbs) restores the CD8+ T cells’ functions, leading to tumor regression. Accordingly, the Food and Drug Administration (FDA) has approved several checkpoint antibodies which act as immune checkpoint inhibitors. Their clinical use in various resistant cancers, such as metastatic melanoma and non-small-cell lung cancer (NSCLC), has shown significant clinical responses. We have investigated an alternative approach to prevent the expression of PD-L1 on tumor cells, through targeting the oncogenic transcription factor Yin Yang 1 (YY1), a known factor overexpressed in many cancers. We report the regulation of PD-L1 by YY1 at the transcriptional, post-transcriptional, and post-translational levels, resulting in the restoration of CD8+ T cells’ anti-tumor functions. We have performed bioinformatic analyses to further explore the relationship between both YY1 and PD-L1 in cancer and to corroborate these findings. In addition to its regulation of PD-L1, YY1 has several other anti-cancer activities, such as the regulation of proliferation and cell viability, invasion, epithelial–mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. Thus, targeting YY1 will have a multitude of anti-tumor activities resulting in a significant obliteration of cancer oncogenic activities. Various strategies are proposed to selectively target YY1 in human cancers and present a promising novel therapeutic approach for treating unresponsive cancer phenotypes. These findings underscore the distinct regulatory roles of YY1 and PD-L1 (CD274) in cancer progression and therapeutic response.

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“…Evidence has shown that the tumor suppressor p53 (TP53) is a regulator of PPP, as it can inhibit the expression of glucose transporters (GLUT1 and GLUT4). Therefore, TP53 could deprive cancer cells of glucose, the primary substrate for PPP [ 60 – 63 ]. Fahong Wu et al [ 33 ] found that ELFN1-AS1 promotes G6PD activity by inducing the degradation of TP53 protein in CRC.…”

Section: Elfn1-as1 Mechanism Of Action In Cancermentioning

confidence: 99%

Role of long non-coding RNA ELFN1-AS1 in carcinogenesis

HajiEsmailpoor,

Fayazi,

Teymouri

et al. 2024

Discov Onc

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As one of the leading causes of death worldwide, cancer significantly burdens patients and the healthcare system. The role of long non-protein coding RNAs (lncRNAs) in carcinogenesis has been extensively studied. The lncRNA ELFN1-AS1 was discovered recently, and subsequent studies have revealed its aberrantly high expression in various cancer tissues. In vitro and in vivo experiments have consistently demonstrated the close association between increased ELFN1-AS1 expression and malignant tumor characteristics, particularly in gastrointestinal malignancies. Functional assays have further revealed the mechanistic role of ELFN1-AS1 as a competitive endogenous RNA for microRNAs, inducing tumor growth, invasive features, and drug resistance. Additionally, the investigation into the clinical implication of ELFN1-AS1 has demonstrated its potential as a diagnostic, therapeutic, and, notably, prognostic marker. This review provides a comprehensive summary of evidence regarding the involvement of ELFN1-AS1 in cancer initiation and development, highlighting its clinical significance.

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Dissecting the roles and clinical potential of YY1 in the tumor microenvironment

Cited by 17 publications

References 135 publications

Vitamin D binding protein (VDBP) hijacks twist1 to inhibit vasculogenic mimicry in hepatocellular carcinoma

Vitamin D binding protein (VDBP) hijacks twist1 to inhibit vasculogenic mimicry in hepatocellular carcinoma

Regulation of PD-L1 Expression by YY1 in Cancer: Therapeutic Efficacy of Targeting YY1

Role of long non-coding RNA ELFN1-AS1 in carcinogenesis

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