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

SIMPLE SUMMARY: New treatments that utilize targeted therapeutic agents or invigorations of the host immune system to destroy cancer cells are not effective against all cancers or responding patients. The mechanism underlying this failure is the ability of cancer cells to escape destruction and remain resistant to therapy. Understanding the gene products that make cancer cells resistant is beneficial in developing new drugs that inhibit resistant factors. One factor controlling the resistance in cancer cells is the gene regulator or transcription factor (TF) Yin Yang 1 (YY1). High levels of YY1 were detected in resistant cancer cells, while the inhibition restored sensitivities to cytotoxic therapies. This review discusses how YY1 overexpression regulates death protective proteins that control cancer cell resistance. Targeting YY1 in cancer cells for its inhibition or targeting its protective proteins will reverse resistance and allow for cancer cells to respond to therapies, tumor regression and the prolongation of survival. 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.