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Review
. 2024 Mar 21;16(6):1237.
doi: 10.3390/cancers16061237.

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

Ana Dillen  1 , Indy Bui  1 , Megan Jung  1 , Stephanie Agioti  2 , Apostolos Zaravinos  2   3 , Benjamin Bonavida  1
Affiliations
Review

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

Ana Dillen et al. Cancers (Basel). .

Abstract

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.

Keywords: PD-L1; T cells; YY1; cancer; immunotherapy; inhibitors; overexpression; resistance.

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Conflict of interest statement

The authors declare no conflicts of interests.

Figures

Figure 2
Figure 2
Effect of the PD-L1/PD-1 interaction on T-cell immune function and cytokines. The modulation of the immune T-cell system occurs when the immune checkpoint PD-L1, present on tumor cells, interacts with PD-1 on CD8 T cells. The interaction of PD-1 and PD-L1 blocks and suppresses T-cell function, including anti-tumor CD8 T cells. Additionally, PD-L1/PD-1 leads to a decrease in the cytokines TNF-α, IFN-γ, and IL-2, allowing for immune escape in tumor cells.
Figure 3
Figure 3
Upregulation and downregulation of PD-L1 by YY1 through various factors. YY1 indirectly regulates the expression of PD-L1 through several factors. YY1 plays a dual role in positively or negatively regulating IFN-γ in different cancers. The downregulation of PD-L1 is achieved when YY1 inhibits IFN-γ or COX-2. YY1 activation of IFN-γ leads to the activation of the JAK1 and STAT1 pathways, contributing to the upregulation of PD-L1 expression. Moreover, YY1 inhibition of PTEN activates the PI3K/Akt pathway, and ultimately, mTOR upregulation increases the expression of PD-L1. IL-6 and TGF-β are activated and inhibited, respectively, by YY1, leading to STAT3 upregulation and increased PD-L1 expression.
Figure 4
Figure 4
YY1 regulation of PD-L1: Epigenetic. Epigenetic regulation of PD-L1 through YY1 is achieved through various proposed mechanisms and relationships. YY1 directly activates EZH2 and, through histone methylation, inhibits PD-L1. Furthermore, YY1 and Stri-201, known inhibitors of STAT3, may indirectly downregulate PD-L1 expression. Next, YY1 has been found to interact with both HDAC5 and HDAC6 in many cancer cells. HDAC6 has a positive relationship with PD-L1, leading to the proposed mechanism between these factors.
Figure 5
Figure 5
Post-translational regulation of PD-L1 expression. YY1 regulates PD-L1 via a post-translational mechanism. Firstly, miR-200 is negatively correlated with YY1, suggesting that miR-200 may decrease YY1 expression. YY1 is a known factor that inhibits p53, and p53 upregulates miR-34a. Ultimately this relationship leads to PD-L1 inhibition, and it is important to further identify ways to target PD-L1.
Figure 6
Figure 6
YY1 regulation of PD-L1: Transcriptional. YY1 regulates PD-L1 transcriptionally through binding to the promoter region found on the PD-L1 CD274 gene. It is also regulated via the p38/MAPK/JNK pathway which upregulates YY1. This causes increased YY1 binding to the PD-L1 promoter and an increase in PD-L1 expression. This interaction leads to cancer progression and T-cell exhaustion of tumor-infiltrating lymphocytes. The red and blue lines represent the DNA helix.
Figure 8
Figure 8
Bioinformatic analysis of PAS between high- and low-YY1 (or CD274)-expressing tumors (A) The heat map shows the percentage of cancers in which the YY1 and CD274 (PD-L1) genes have an activating (red) or inhibitory (blue) effect (FDR ≤ 0.05) on 10 cancer-related pathways, across 32 TCGA cancer types. The number in each cell indicates the corresponding percentage. (B) Two examples of the activity of the Cell Cycle pathway between high- and low-YY1-expressing breast cancers, as well as of the activity of the Apoptosis pathway between high- and low-CD274 (PD-L1)-expressing breast cancers (TCGA-BRCA).
Figure 1
Figure 1
YY1 regulation of cellular processes and its role in cancer cells. YY1 is an activator or repressor in several cellular processes including gene expression, apoptosis, DNA repair, cellular metabolism, cell survival, cellular differentiation, and cell cycle regulation. Disruption of YY1 signaling and overexpression of YY1 in cancer is associated with metastasis, resistance to chemotherapy and immunotherapy in cancer patients, and poor prognosis in patients [55,56]. Figure 1, Figure 2, Figure 3, Figure 4, Figure 5 and Figure 6 were generated using https://www.biorender.com/ accessed on 12 January 2023.
Figure 7
Figure 7
YY1-mediated regulation of PD-L1 and EMT. YY1 is an important therapeutic target due to its role in the regulation of the EMT and PD-L1. Through the NF-κB/Snail/YY1/RKIP loop, YY1 can be targeted to modulate the EMT, an important factor for immune escape in cancer cells. Additionally, YY1 upregulates PD-L1, leading to an increase in the PD-L1/PD-1 interaction. This leads to T-cell exhaustion, immune tolerance of tumor cells, and cancer progression.
Figure 9
Figure 9
Various targets that lead to the inhibition of YY1. Through the inhibition of YY1 and PD-L1 downregulation, oncogenic effects may decrease. Several targets are identified to achieve negative regulation of YY1. RKIP is a target that has a known inverse relationship with YY1 through the NF-κB/Snail/YY1/RKIP loop. NO is also implicated with the inhibition of YY1 through the repression of SNAIL, while NF-κB is also a promising factor to consider in the context of the NF-κB/SNAIL/YY1/RKIP/PTEN loop. ASOs also provide specificity in inhibiting YY1 through their ability to bind to specific RNA target sequences. Next, the use of miR-7, miR-34a, miR-489, or miR-193a-5p may have the ability to regulate YY1 gene expression negatively. The use of gRNAs through CRISPR/Cas9 may block YY1 gene function through disruption of the DNA sequence. The use of a novel synthetic small-molecule inhibitor, Inh-YY1, may directly inhibit the DNA-binding activity of YY1. Finally, YY1-targeted nanoparticle delivery is a promising selective method of YY1 inhibition. It is proposed to be used in combination with other methods of YY1 inhibition as previously mentioned.
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