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

Abstract

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.

The role of USP7-YY1 interaction in promoting colorectal cancer growth and metastasis

“…The significance of YY1 in oncogenic pathways has sparked extensive research efforts aimed at inhibiting YY1 through various direct and indirect targets for therapeutic purposes [ 41 ]. The reported strategies for inducing YY1 inhibition include direct phosphorylation, increasing ubiquitination, microRNA regulation, betulinic acid, and NO donors [ 42 , 43 ].…”

“…The reported strategies for inducing YY1 inhibition include direct phosphorylation, increasing ubiquitination, microRNA regulation, betulinic acid, and NO donors [ 42 , 43 ]. Additionally, a small synthetic inhibitor of YY1 (Inh-YY1) is currently in development, offering promise in addressing the need for a specific YY1 inhibitor [ 41 ]. On the other hand, several USP7 inhibitors have been identified, showing encouraging results in vitro and in vivo studies.…”

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

“…The cell cycle is regulated by YY1 through its promotion or suppression of a number of genes [ 58 ]. Additionally, YY1 promotes cell survival by regulating anti-apoptotic factors and signaling pathways [ 59 , 60 , 61 ]. Cell development and differentiation are also influenced by YY1 due to its control of gene expression patterns [ 41 , 44 , 62 , 63 ].…”

“…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 ].…”

“…In CRC, the overexpression of miR-7 is correlated with the inhibition of proliferation, induction of apoptosis, and induced cell arrest in G1 [ 75 , 247 ]. MiR-7 directly binds to YY1 and downregulates YY1 expression in CRC, ultimately inducing apoptosis [ 59 , 75 , 198 ]. Furthermore, studies focused on cervical cancer cases found that miR-181 negatively regulates YY1 expression and additionally inhibits tumor cell proliferation [ 248 ].…”