Core transcriptional regulatory circuitries in cancer

Chen, Ye; Xu, Lu; Lin, Ruby Yu-Tong; Müschen, Markus; Koeffler, H. Phillip

doi:10.1038/s41388-020-01459-w

Cited by 45 publications

(45 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transcription addiction contributes to the uncontrolled cell proliferation of tumors. Therefore, therapeutically targeting of transcription factors is an attractive target for tumor therapy (34). CDK7 is a transcription addiction factor that is upregulated in various types of tumor and correlated with prognosis of patients (5).…”

Section: Discussionmentioning

confidence: 99%

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

Abudureheman

Xia

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

B-cell acute lymphocytic leukemia (B-ALL) is a malignant blood cancer that develops in children and adults and leads to high mortality. THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains obscure. In this study, we showed that THZ1 arrested the cell cycle of B-ALL cells in vitro in a low concentration, while inducing the apoptosis of B-ALL cells in vitro in a high concentration by activating the apoptotic pathways. In addition, RNA-SEQ results revealed that THZ1 disrupted the cellular metabolic pathways of B-ALL cells. Moreover, THZ1 suppressed the cellular metabolism and blocked the production of cellular metabolic intermediates in B-ALL cells. Mechanistically, THZ1 inhibited the cellular metabolism of B-ALL by downregulating the expression of c-MYC-mediated metabolic enzymes. However, THZ1 treatment enhanced cell apoptosis in over-expressed c-MYC B-ALL cells, which was involved in the upregulation of p53 expression. Collectively, our data demonstrated that CDK7 inhibitor THZ1 induced the apoptosis of B-ALL cells by perturbing c-MYC-mediated cellular metabolism, thereby providing a novel treatment option for B-ALL.

show abstract

Section: Discussionmentioning

confidence: 99%

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

Abudureheman

Xia

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…CRC TFs bind to cell-type-specific enhancers and regulate the expression of cell-type-specific genes 80 .…”

Section: Discussionmentioning

confidence: 99%

Integrative genomics identifies lncRNA regulatory networks across 1,044 pediatric leukemias and extra-cranial solid tumors

Modi

López

Conkrite

et al. 2020

Preprint

View full text Add to dashboard Cite

Long non-coding RNAs (lncRNAs) play an important role in gene regulation and can contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curate RNA sequencing data for 1,044 pediatric leukemia and solid tumors and integrate paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. We report a total of 2,657 robustly expressed lncRNAs across six pediatric cancers, including 1,142 lncRNAs exhibiting histotype-specific expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Analysis of upstream regulation via tissue-specific, oncogenic transcription factors further implicated 608 distinct histotype-associated lncRNAs. Application of a multi-dimensional framework to identify and prioritize lncRNAs impacting entire gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage pathways. Silencing TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for hypothesis-driven mechanistic studies.

show abstract

“…On the other hand, expression of master TFs that bind SEs is often regulated by the activity of SEs, indicating the existence of a positive feedback regulation between SEs and master TFs. Indeed, core regulatory circuitry (CRC) has been established in both normal (e.g., embryonic stem cells (ESCs)) and malignant cells [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] . In such regulatory circuitries, master TFs form an auto-regulated loop with SEs of themselves, as well as an interconnected loop with other master TFs and their SEs, resulting high expression levels of each TF within CRC.…”

Section: Introductionmentioning

confidence: 99%

“…As a result, the CRC structure is relatively stable and robust. Nevertheless, considering the prominent role of CRC in cancer, it serves as an attractive target [8] , [11] , [13] , [17] . Indeed, by perturbing the activity of various transcriptional regulatory components, including RNA polymerase II-dependent elongation, chromatin architecture and SE activity, transcriptional and epigenetic inhibitors such as CDK7 inhibitor, BET and HDAC inhibitors have shown encouraging anti-neoplastic potential in (pre)clinical trials in various types of malignancies [3] , [11] , [13] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] , [26] .…”

Section: Introductionmentioning

confidence: 99%

Super-enhancer-mediated core regulatory circuitry in human cancer

Jiang

Lin

2021

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

Super-enhancers (SEs) are congregated enhancer clusters with high level of loading of transcription factors (TFs), cofactors and epigenetic modifications. Through direct co-occupancy at their own SEs as well as each other’s, a small set of so called “master” TFs form interconnected core regulatory circuitry (CRCs) to orchestrate transcriptional programs in both normal and malignant cells. These master TFs can be predicted mathematically using epigenomic methods. In this Review, we summarize the identification of SEs and CRCs in cancer cells, the mechanisms by which master TFs and SEs cooperatively regulate cancer-type-specific expression programs, and the cancer-type- and subtype-specificity of CRC and the significance in cancer biology.

show abstract

Core transcriptional regulatory circuitries in cancer

Cited by 45 publications

References 90 publications

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

Integrative genomics identifies lncRNA regulatory networks across 1,044 pediatric leukemias and extra-cranial solid tumors

Super-enhancer-mediated core regulatory circuitry in human cancer

Contact Info

Product

Resources

About