Cell-cycle arrest and senescence in TP53-wild type renal carcinoma by enhancer RNA-P53-bound enhancer regions 2 (p53BER2) in a p53-dependent pathway

Xie, Haibiao; Ma, Kaifang; Zhang, Kenan; Zhou, Jingcheng; Li, Lei; Yang, Wuping; Gong, Yanqing; Cai, Lin; Gong, Kan

doi:10.1038/s41419-020-03229-8

Cited by 154 publications

(73 citation statements)

References 48 publications

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“…Restoration of miR-122 expression in HCC results in suppression of tumor growth and metastasis, and enhances chemosensitivity, suggesting that miR-122 functions as a tumor suppressor against HCC [ 47 ]. To date, several target genes of miR-122, such as cyclin G1, a disintegrin, and metalloprotease 10 (ADAM10), Wnt family member 1, Snail1/2, and pyruvate kinase M2, were identified to modulate hepatocarcinogenesis, the EMT, angiogenesis, and metabolism of HCC [ 47 , 48 , 49 , 50 , 51 ]. Our results indicated that G9a represents a novel, important target gene of miR-122 in regulating HCC progression.…”

Section: Discussionmentioning

confidence: 99%

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122

Yuan

Lee

Yang

et al. 2021

Cancers

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Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers, which is the second most lethal tumor worldwide. Epigenetic deregulation is a common trait observed in HCC. Recently, increasing evidence suggested that the G9a histone methyltransferase might be a novel regulator of HCC development. However, several HCC cell lines were recently noted to have HeLa cell contamination or to have been derived from non-hepatocellular origin, suggesting that functional validation of G9a in proper HCC models is still required. Herein, we first confirmed that higher G9a messenger RNA and protein expression levels were correlated with poor overall survival (OS) and disease-free survival (DFS) rates of HCC patients from The Cancer Genome Atlas (TCGA) dataset and our recruited HCC cohort. In an in vitro functional evaluation of HCC cells, HCC36 (hepatitis B virus-positive (HBV+) and Mahlavu (HBV−)) cells showed that G9a participated in promoting cell proliferation, colony formation, and migration/invasion abilities. Moreover, orthotopic inoculation of G9a-depleted Mahlavu cells in NOD-SCID mice also resulted in a significantly decreased tumor burden compared to the control group. Furthermore, after surveying microRNA (miRNA; miR) prediction databases, we identified the liver-specific miR-122 as a G9a-targeting miRNA. In various HCC cell lines, we observed that miR-122 expression levels tended to be inversely correlated to G9a expression levels. In clinical HCC specimens, a significant inverse correlation of miR-122 and G9a mRNA expression levels was also observed. Functionally, the colony formation and invasive ability were attenuated in miR-122-overexpressing HCC cells. HCC patients with low miR-122 and high G9a expression levels had the worst OS and DFS rates compared to others. Together, our results confirmed the importance of altered G9a expression during HCC progression and discovered that a novel liver-specific miR-122-G9a regulatory axis exists.

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Section: Discussionmentioning

confidence: 99%

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122

Yuan

Lee

Yang

et al. 2021

Cancers

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“…Trx-1 is a validated cancer drug target that is involved in many of the hallmarks of cancer including increased proliferation, resistance to cell death, and increased angiogenesis [ 163 ]. Recent studies have shown that overexpression of a gene SIRT6, through regulating HIF-1α, promoted invasion, migration, proliferation, and angiogenesis [ 164 ].…”

Section: Mechanism Of Oxidative Stress-related Carcinogenesismentioning

confidence: 99%

Oxidative Stress in Cancer Cell Metabolism

et al. 2021

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Reactive oxygen species (ROS) are important in regulating normal cellular processes whereas deregulated ROS leads to the development of a diseased state in humans including cancers. Several studies have been found to be marked with increased ROS production which activates pro-tumorigenic signaling, enhances cell survival and proliferation and drives DNA damage and genetic instability. However, higher ROS levels have been found to promote anti-tumorigenic signaling by initiating oxidative stress-induced tumor cell death. Tumor cells develop a mechanism where they adjust to the high ROS by expressing elevated levels of antioxidant proteins to detoxify them while maintaining pro-tumorigenic signaling and resistance to apoptosis. Therefore, ROS manipulation can be a potential target for cancer therapies as cancer cells present an altered redox balance in comparison to their normal counterparts. In this review, we aim to provide an overview of the generation and sources of ROS within tumor cells, ROS-associated signaling pathways, their regulation by antioxidant defense systems, as well as the effect of elevated ROS production in tumor progression. It will provide an insight into how pro- and anti-tumorigenic ROS signaling pathways could be manipulated during the treatment of cancer.

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“…Mouse xenograft models of A375 cells with stable knock-down of CSN6 manifested significantly smaller tumors and CDK9 positive cells, as compared to those derived from CSN6 expressing cells. These effects of CSN6 knock-down could be significantly rescued by concurrent knock-down of UBR5, highlighting the significance of CDK9 in melanoma [ 113 ]. As CSN6 expression is up-regulated in multiple cancer entities [ 113 , 114 , 115 ], it stands to reason that this effect, demonstrated in melanoma could occur in other cancer types too.…”

Section: The Clinical Relevance Of Cdk9mentioning

confidence: 99%

Targeting CDK9 for Anti-Cancer Therapeutics

Mandal

Becker

Strebhardt

2021

Cancers

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Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription regulatory members of the CDK family. In conjunction with its main cyclin partner—Cyclin T1, it forms the Positive Transcription Elongation Factor b (P-TEFb) whose primary function in eukaryotic cells is to mediate the positive transcription elongation of nascent mRNA strands, by phosphorylating the S2 residues of the YSPTSPS tandem repeats at the C-terminus domain (CTD) of RNA Polymerase II (RNAP II). To aid in this process, P-TEFb also simultaneously phosphorylates and inactivates a number of negative transcription regulators like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) Sensitivity-Inducing Factor (DSIF) and Negative Elongation Factor (NELF). Significantly enhanced activity of CDK9 is observed in multiple cancer types, which is universally associated with significantly shortened Overall Survival (OS) of the patients. In these cancer types, CDK9 regulates a plethora of cellular functions including proliferation, survival, cell cycle regulation, DNA damage repair and metastasis. Due to the extremely critical role of CDK9 in cancer cells, inhibiting its functions has been the subject of intense research, resulting the development of multiple, increasingly specific small-molecule inhibitors, some of which are presently in clinical trials. The search for newer generation CDK9 inhibitors with higher specificity and lower potential toxicities and suitable combination therapies continues. In fact, the Phase I clinical trials of the latest, highly specific CDK9 inhibitor BAY1251152, against different solid tumors have shown good anti-tumor and on-target activities and pharmacokinetics, combined with manageable safety profile while the phase I and II clinical trials of another inhibitor AT-7519 have been undertaken or are undergoing. To enhance the effectiveness and target diversity and reduce potential drug-resistance, the future of CDK9 inhibition would likely involve combining CDK9 inhibitors with inhibitors like those against BRD4, SEC, MYC, MCL-1 and HSP90.

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Cell-cycle arrest and senescence in TP53-wild type renal carcinoma by enhancer RNA-P53-bound enhancer regions 2 (p53BER2) in a p53-dependent pathway

Cited by 154 publications

References 48 publications

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122

Oxidative Stress in Cancer Cell Metabolism

Targeting CDK9 for Anti-Cancer Therapeutics

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