The role of transcription factor Yin Yang‐1 in colorectal cancer

Cancer is a leading cause of death among the various diseases encountered in humans. Cancer is not a single entity and consists of numerous different types and subtypes that require various treatment regimens. In the last decade, several milestones in cancer treatments were accomplished, such as specific targeting agents or revitalizing the dormant anti-tumor immune response. These milestones have resulted in significant positive clinical responses as well as tumor regression and the prolongation of survival in subsets of cancer patients. Hence, in non-responding patients and non-responding relapsed patients, cancers develop intrinsic mechanisms of resistance to cell death via the overexpression of anti-apoptotic gene products. In parallel, the majority of resistant cancers have been reported to overexpress a transcription factor, Yin Yang 1 (YY1), which regulates the chemo-immuno-resistance of cancer cells to therapeutic anticancer cytotoxic agents. The relationship between the overexpression of YY1 and several anti-apoptotic gene products, such as B-cell lymphoma 2 protein (Bcl-2), B-cell lymphoma extra-large (Bcl-xL), myeloid cell leukemia 1 (Mcl-1) and survivin, is investigated in this paper. The findings demonstrate that these anti-apoptotic gene products are regulated, in part, by YY1 at the transcriptional, epigenetic, post-transcriptional and translational levels. While targeting each of the anti-apoptotic gene products individually has been examined and clinically tested for some, this targeting strategy is not effective due to compensation by other overexpressed anti-apoptotic gene products. In contrast, targeting YY1 directly, through small interfering RNAs (siRNAs), gene editing or small molecule inhibitors, can be therapeutically more effective and generalized in YY1-overexpressed resistant cancers.

Section: Mcl-1mentioning

confidence: 99%

Role of YY1 in the Regulation of Anti-Apoptotic Gene Products in Drug-Resistant Cancer Cells

Jung,

Bui,

Bonavida

2023

“…Moreover, utilizing miRNAs to downregulate YY1 expression led to beneficial outcomes in melanoma patients due to the inhibition of the EMT [ 107 , 216 ]. More recently, YY1 regulation has been linked to the overexpression of several anti-apoptotic factors including Bcl-2, Bcl-xL, Mcl-1, and survivin [ 59 , 217 , 218 , 219 , 220 ]. Within the NF-κB/Snail/YY1/RKIP loop regulating the EMT, an inverse relationship between YY1 and RKIP exists, suggesting an additional potential source for indirect YY1 inhibition [ 74 , 221 ].…”

Section: Therapeutic Targeting Of Yy1 For Immune Checkpoint Blockadementioning

confidence: 99%

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

Dillen,

Bui,

Jung

et al. 2024

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.

“…These findings agree with other reported studies demonstrating that YY1 transcriptionally regulates all of the above immune checkpoints. Briefly, Shao et al [ 66 ] and Chandnani et al [ 67 ] have recently reported the regulation of SIGLEC-15 by YY1. Likewise, Dulal et al [ 68 ] and Ziogas et al [ 69 ] recently reported the regulation of TIGIT by YY1.…”

Section: Bioinformatics Analysis Of Yy1 Expression In Gbmmentioning

confidence: 99%

Therapeutic Implications of Targeting YY1 in Glioblastoma

Navasardyan,

Zaravinos,

Bonavida

2024

The transcription factor Yin Yang 1 (YY1) plays a pivotal role in the pathogenesis of glioblastoma multiforme (GBM), an aggressive form of brain tumor. This review systematically explores the diverse roles of YY1 overexpression and activities in GBM, including its impact on the tumor microenvironment (TME) and immune evasion mechanisms. Due to the poor response of GBM to current therapies, various findings of YY1-associated pathways in the literature provide valuable insights into novel potential targeted therapeutic strategies. Moreover, YY1 acts as a significant regulator of immune checkpoint molecules and, thus, is a candidate therapeutic target in combination with immune checkpoint inhibitors. Different therapeutic implications targeting YY1 in GBM and its inherent associated challenges encompass the use of nanoparticles, YY1 inhibitors, targeted gene therapy, and exosome-based delivery systems. Despite the inherent complexities of such methods, the successful targeting of YY1 emerges as a promising avenue for reshaping GBM treatment strategies, presenting opportunities for innovative therapeutic approaches and enhanced patient outcomes.