bims-ectoca 2023-01-22 papers

Cancers (Basel). 2023 Jan 11. pii: 466. [Epub ahead of print]15(2):

Chromatin and Cancer: Implications of Disrupted Chromatin Organization in Tumorigenesis and Its Diversification.

A hallmark of cancers is uncontrolled cell proliferation, frequently associated with an underlying imbalance in gene expression. This transcriptional dysregulation observed in cancers is multifaceted and involves chromosomal rearrangements, chimeric transcription factors, or altered epigenetic marks. Traditionally, chromatin dysregulation in cancers has been considered a downstream effect of driver mutations. However, here we present a broader perspective on the alteration of chromatin organization in the establishment, diversification, and therapeutic resistance of cancers. We hypothesize that the chromatin organization controls the accessibility of the transcriptional machinery to regulate gene expression in cancerous cells and preserves the structural integrity of the nucleus by regulating nuclear volume. Disruption of this large-scale chromatin in proliferating cancerous cells in conventional chemotherapies induces DNA damage and provides a positive feedback loop for chromatin rearrangements and tumor diversification. Consequently, the surviving cells from these chemotherapies become tolerant to higher doses of the therapeutic reagents, which are significantly toxic to normal cells. Furthermore, the disorganization of chromatin induced by these therapies accentuates nuclear fragility, thereby increasing the invasive potential of these tumors. Therefore, we believe that understanding the changes in chromatin organization in cancerous cells is expected to deliver more effective pharmacological interventions with minimal effects on non-cancerous cells.

Keywords: cancer; chromatin; epigenetic; gene expression; nucleus; therapeutics

DOI: https://doi.org/10.3390/cancers15020466

Proc Natl Acad Sci U S A. 2023 Jan 24. 120(4): e2216436120

Enhancer-promoter entanglement explains their transcriptional interdependence.

Anil K Panigrahi, David M Lonard, Bert W O'Malley.

Enhancers not only activate target promoters to stimulate messenger RNA (mRNA) synthesis, but they themselves also undergo transcription to produce enhancer RNAs (eRNAs), the significance of which is not well understood. Transcription at the participating enhancer-promoter pair appears coordinated, but it is unclear why and how. Here, we employ cell-free transcription assays using constructs derived from the human GREB1 locus to demonstrate that transcription at an enhancer and its target promoter is interdependent. This interdependence is observable under conditions where direct enhancer-promoter contact (EPC) takes place. We demonstrate that transcription activation at a participating enhancer-promoter pair is dependent on i) the mutual availability of the enhancer and promoter, ii) the state of transcription at both the enhancer and promoter, iii) local abundance of both eRNA and mRNA, and iv) direct EPC. Our results suggest transcriptional interdependence between the enhancer and the promoter as the basis of their transcriptional concurrence and coordination throughout the genome. We propose a model where transcriptional concurrence, coordination and interdependence are possible if the participating enhancer and promoter are entangled in the form of EPC, reside in a proteinaceous bubble, and utilize shared transcriptional resources and regulatory inputs.

Keywords: eRNA; enhancer–promoter contact; transcription activation

DOI: https://doi.org/10.1073/pnas.2216436120

J Chemother. 2023 Jan 19. 1-11

YAP/TAZ axis was involved in the effects of metformin on breast cancer.

Yu Xu, Hongke Cai, Yuanfeng Xiong, Li Tang, Longjiang Li, Li Zhang, Yi Shen, Yongqiang Yang, Ling Lin, Jiayi Huang.

Breast cancer is malignant tumours in women. A large amount of data analysis shows that Metformin has been shown to play a significance role in reducing the risk of breast cancer, but the mechanism remains unclear. The hippo signalling pathway can be involved in the formation, metastasis and recurrence of breast cancer. When YAP/TAZ is activated, cells can overcome contact inhibition and enter a state of uncontrolled proliferation. Therefore, YAP/TAZ is considered a potential therapeutic target for breast cancer. Eighty breast cancer patients, forty cases of triple-negative and forty cases of HER-2+, were included in this study. In vitro and in vivo experiments were used to confirm the YAP/TAZ axis was involved in the effects of metformin on breast cancer. EMT plays an important role in breast cancer, including chemoresistance and tumour metastasis. Our results confirmed that YAP could modulate the activity of EMT, which in turn altered tumour resistance. Therefore, MET can inhibit EMT by reducing the expression of YAP, and finally achieve the therapeutic effect of breast cancer. Our findings support metformin as a novel YAP inhibitor and potentially as a novel breast cancer drug.

Keywords: Metformin; YAP/TAZ activity; breast cancer; epithelial–mesenchymal transition; hippo signalling pathway; novel drug; nuclear translocation

DOI: https://doi.org/10.1080/1120009X.2022.2162221

FEBS Lett. 2023 Jan 17.

CCDC115 inhibits autophagy-mediated degradation of YAP to promote cell proliferation.

Hui Feng, Xiao Liu, Chenqian Zhou, Qiuchen Gu, Ye Li, Jianguo Chen, Junlin Teng, Pengli Zheng.

Autophagy and Hippo signaling pathways both play important roles in cell homeostasis and are often involved in tumorigenesis. However, the crosstalk between these two signal pathways in response to stress conditions, such as nutrient deficiency, is incompletely understood. Here, we show that vesicular localized coiled-coil domain containing 115 (CCDC115) inhibits autophagy as well as Hippo signaling pathway under starvation. Moreover, we show that CCDC115 interacts with the HOPS complex. This interaction competes with STX17, thus inhibiting the fusion of autophagosomes with lysosomes. Hence, CCDC115 inhibits the autophagic degradation of yes-associated protein (YAP), thereby promoting cell proliferation in nutrient-restricted situation.

Keywords: CCDC115; HOPS complex; Hippo pathway; YAP; autophagy; cell proliferation

DOI: https://doi.org/10.1002/1873-3468.14575