There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.

YY1 Is a Structural Regulator of Enhancer-Promoter Loops

Zinc enhances TCR signaling in part by inhibiting Shp-1 recruitment to the TCR synapse.

Regulation of T-cell receptor signaling by activation-induced zinc influx

https://www.cell.com/cancer-cell/pdf/S1535-6108(19)30523-9.pdf

CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer

MYC as a target for cancer treatment.

Yin Yang 1 (YY1), a dual function transcription factor, is known to regulate transcriptional activation and repression of many genes associated with multiple cellular processes including cellular differentiation, DNA repair, autophagy, cell survival vs. apoptosis, and cell division. Owing to its role in processes that upon deregulation are linked to malignant transformation, YY1 has been implicated as a major driver of many cancers. While a large body of evidence supports the role of YY1 as a tumor promoter, recent reports indicated that YY1 also functions as a tumor suppressor. The mechanism by which YY1 brings out opposing outcome in tumor growth vs. suppression is not completely clear and some of the recent reports have provided significant insight into this. Likewise, the mechanism by which YY1 functions both as a transcriptional activator and repressor is not completely clear. It is likely that the proteins with which YY1 interacts might determine its function as an activator or repressor of transcription as well as its role as a tumor suppressor or promoter. Hence, a collection of YY1-protein interactions in the context of different cancers would help us gain an insight into how YY1 promotes or suppresses cancers. This review focuses on the YY1 interacting partners and its target genes in different cancer models. Finally, we discuss the possibility of therapeutically targeting the YY1 in cancers where it functions as a tumor promoter.

The Two Sides of YY1 in Cancer: A Friend and a Foe.

Human MYC G-quadruplex: From discovery to a cancer therapeutic target.

Prostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer-related death among men worldwide. Despite progresses in early diagnosis and therapeutic strategies, prognosis for patients with advanced PCa remains poor. Noteworthily, a unique feature of healthy prostate is its highest level of zinc content among all soft tissues in the human body, which dramatically decreases during prostate tumorigenesis. To date, several reviews have suggested antitumor activities of zinc and its potential as a therapeutic strategy of PCa. However, an overview about the role of zinc and its signaling in PCa is needed. Here, we review literature related to the content, biological function, compounds and clinical application of zinc in PCa. We first summarize zinc content in prostate tissue and sera of PCa patients with their clinical relevance. We then elaborate biological functions of zinc signaling in PCa on three main aspects, including cell proliferation, death and tumor metastasis. Finally, we discuss clinical applications of zinc-containing compounds and proteins involved in PCa signaling pathways. Based on currently available studies, we conclude that zinc plays a tumor suppressive role and can serve as a biomarker in PCa diagnosis and therapies.

https://www.mdpi.com/1422-0067/21/2/667/pdf

Advances of Zinc Signaling Studies in Prostate Cancer.

Thymoquinone (TQ) is a natural compound extracted from the black seeds of Nigella sativa Linn. belonging to the Ranunculaceae family. TQ exhibits anti-inflammatory and antineoplastic activities against various cancers. Many therapeutics in hepatocellular carcinoma (HCC) treatments, such as doxorubicin (DOX) and cisplatin (DDP), exhibit considerable side effects on patients. We investigated cytotoxic effects of TQ, alone or in combination with DDP and DOX to HCC cells. TQ exhibited selective killing to HCC HepG2 and SMMC-7721 cells, but relatively low toxicity to normal liver HL-7702 cells. Importantly, when used with DOX or DDP, TQ showed synergistic inhibition of HCC cells, but not HL-7702 cells. We also discovered that Hep3B cells with a p53 null status were more sensitive to TQ than HepG2 and SMMC-7721 cells harboring wild type p53. Consistently, shRNA-mediated p53 silencing in HepG2 cells dramatically enhanced TQ-induced apoptosis, measured by caspase 3 and PARP cleavage. Furthermore, TQ-stimulated increase of reactive oxygen species (ROS) in p53-depleted cells was more pronounced than that in cells with intact p53. In summary, we discovered that TQ synergistically improves the anti-cancer activity of DOX and DDP, and loss of p53 sensitizes HCC cells to TQ-induced apoptosis.

/pdf/thymoquinone-selectively-induces-hepatocellular-carcinoma-88wcm79np2.pdf

Thymoquinone Selectively Induces Hepatocellular Carcinoma Cell Apoptosis in Synergism With Clinical Therapeutics and Dependence of p53 Status.

Yin Yang 1 (YY1) is a member of the GLI-Kruppel family of zinc finger proteins that plays vital roles in many biological processes, especially tumorigenesis. To date, ample evidence suggests a critical regulatory role of YY1 in tumor cell metastasis. The potential of YY1 as a valuable biomarker for cancer metastasis has been increasingly known. Here, we review the studies related to the expression, regulatory network, and clinical application of YY1 in cancer metastasis. We first summarize YY1 expression patterns in metastatic tumors. We then elaborate YY1-regulated mechanisms on five aspects, including epithelial-mesenchymal transition, cell migration and invasion, stemness, polyploidy, and genomic stability. Finally, we discuss the correlation between YY1 expression and clinical outcomes and therapeutic potential of YY1 in cancer treatment. Based on this review, we conclude that YY1 is a bona fide inducer of cancer metastasis and can serve as a clinical biomarker and therapeutic target for cancer treatment.

YY1 Is an Inducer of Cancer Metastasis

Abstract As an oncogenic transcription factor, Yin Yang 1 (YY1) regulates enhancer and promoter connection. However, gaps still exist in understanding how YY1 coordinates coactivators and chromatin enhancer elements to assemble enhancers and super-enhancers. Here, we demonstrate that a histidine cluster in YY1’s transactivation domain is essential for its formation of phase separation condensates, which can be extended to additional proteins. The histidine cluster is also required for YY1-promoted cell proliferation, migration, clonogenicity and tumor growth. YY1-rich nuclear puncta contain coactivators EP300, BRD4, MED1 and active RNA polymerase II, and colocalize with histone markers of gene activation, but not that of repression. Furthermore, YY1 binds to the consensus motifs in the FOXM1 promoter to activate its expression. Wild-type YY1, but not its phase separation defective mutant, connects multiple enhancer elements and the FOXM1 promoter to form an enhancer cluster. Consistently, fluorescent in situ hybridization (FISH) assays reveal the colocalization of YY1 puncta with both the FOXM1 gene locus and its nascent RNA transcript. Overall, this study demonstrates that YY1 activates target gene expression through forming liquid-liquid phase separation condensates to compartmentalize both coactivators and enhancer elements, and the histidine cluster of YY1 plays a determinant role in this regulatory mechanism.

/pdf/a-histidine-cluster-determines-yy1-compartmentalized-1iddz8as.pdf

Dangdang Li

Papers

Human MYC G-quadruplex: From discovery to a cancer therapeutic target.

Advances of Zinc Signaling Studies in Prostate Cancer.

Thymoquinone Selectively Induces Hepatocellular Carcinoma Cell Apoptosis in Synergism With Clinical Therapeutics and Dependence of p53 Status.

YY1 Is an Inducer of Cancer Metastasis

A histidine cluster determines YY1-compartmentalized coactivators and chromatin elements in phase-separated enhancer clusters