bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023–10–22
six papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Comparison of cell response to chromatin and DNA damage.
  2. Pan-cancer analysis of the oncogenic role of the core osteosarcoma gene VCAN in human tumors.
  3. Involvement of CCCTC-binding factor in epigenetic regulation of cancer.
  4. YAP nuclear translocation induced by HIF-1α prevents DNA damage under hypoxic conditions.
  5. In silico screening and identification of potential drug against p300 acetyltransferase activity in breast cancer via drug repurposing approach.
  6. Analyzing histone ChIP-seq data with a bin-based probability of being signal.
  1. Nucleic Acids Res. 2023 Oct 19. pii: gkad865. [Epub ahead of print]
    Comparison of cell response to chromatin and DNA damage.
    Artyom Luzhin, Priyanka Rajan, Alfiya Safina, Katerina Leonova, Aimee Stablewski, Jianmin Wang, Denisha Robinson, Natalia Isaeva, Omar Kantidze, Katerina Gurova.
      DNA-targeting drugs are widely used for anti-cancer treatment. Many of these drugs cause different types of DNA damage, i.e. alterations in the chemical structure of DNA molecule. However, molecules binding to DNA may also interfere with DNA packing into chromatin. Interestingly, some molecules do not cause any changes in DNA chemical structure but interfere with DNA binding to histones and nucleosome wrapping. This results in histone loss from chromatin and destabilization of nucleosomes, a phenomenon that we call chromatin damage. Although the cellular response to DNA damage is well-studied, the consequences of chromatin damage are not. Moreover, many drugs used to study DNA damage also cause chromatin damage, therefore there is no clarity on which effects are caused by DNA or chromatin damage. In this study, we aimed to clarify this issue. We treated normal and tumor cells with bleomycin, nuclease mimicking drug which cut predominantly nucleosome-free DNA and therefore causes DNA damage in the form of DNA breaks, and CBL0137, which causes chromatin damage without direct DNA damage. We describe similarities and differences between the consequences of DNA and chromatin damage. Both agents were more toxic for tumor than normal cells, but while DNA damage causes senescence in both normal and tumor cells, chromatin damage does not. Both agents activated p53, but chromatin damage leads to the accumulation of higher levels of unmodified p53, which transcriptional activity was similar to or lower than that of p53 activated by DNA damage. Most importantly, we found that while transcriptional changes caused by DNA damage are limited by p53-dependent activation of a small number of p53 targets, chromatin damage activated many folds more genes in p53 independent manner.
    DOI:  https://doi.org/10.1093/nar/gkad865
  2. Am J Transl Res. 2023 ;15(9): 5556-5573
    Pan-cancer analysis of the oncogenic role of the core osteosarcoma gene VCAN in human tumors.
    Haidong Zhou, Dinggui Lu, Dianbo Yu, Changtai Luo, Kangqi Xie, Huade Ma, Shanlang Li, Jiyun Liang, Fengxu Wei, Luchang Chen, Dong Luo, Wei Wang, Jihua Wei.
       OBJECTIVE: Versican (VCAN), a member of the multifunctional glycoprotein family, is involved in various aspects of cancer progression. However, the role of VCAN in diverse cancers remains poorly defined. This research aimed to investigate the correlation between VCAN expression and the oncogenic role, as well as visualize its prognostic landscape in pan-cancer.
    METHODS: Raw data in regard to VCAN expression in cancer patients were acquired from GEO GeneChip public database in NCBI. Besides, we selected microarray data GSE16088 for analysis. We retrieved the genes associated with osteosarcoma (OS) from the OMIM database and identified their intersection with the core module. VCAN was suggested to be a potential marker gene for OS. Subsequently, we conducted Gene Set Enrichment Analysis (GSEA) to explore gene functional enrichment. Moreover, we performed pan-cancer analysis on VCAN to gain a comprehensive understanding of its implications across various cancer types.
    RESULTS: The VCAN expression in the tumor tissue was higher than that in normal tissue. Elevated expression of VCAN was associated with high the tumor stage and poor long-term survival. There was a significant positive correlation between VCAN and cancer fibroblasts in all pan cancers. Moreover, FBN1 was the intersection gene of VCAN-related genes and linker genes. ANTXR1, COL5A2, CSGALNACT2, and SPARC were the target genes of VCAN genes. GSEA analysis showed that VCAN was mainly enriched in the extracellular matrix (ECM) signaling pathway.
    CONCLUSION: VCAN can be used as a marker molecule for the early diagnosis of OS and holds significance as a molecule in cases of OS with distant metastasis. The ECM signaling pathway may be a core pathway in OS development and distant metastasis. These findings shed new light on therapeutics of cancers.
    Keywords:  ECM signaling pathway; Osteosarcoma; VCAN; pan cancer; transfer
  3. Mol Biol Rep. 2023 Oct 15.
    Involvement of CCCTC-binding factor in epigenetic regulation of cancer.
    Sayani Bose, Srawsta Saha, Harsita Goswami, Geetha Shanmugam, Koustav Sarkar.
      A major global health burden continues to be borne by the complex and multifaceted disease of cancer. Epigenetic changes, which are essential for the emergence and spread of cancer, have drawn a huge amount of attention recently. The CCCTC-binding factor (CTCF), which takes part in a wide range of cellular processes including genomic imprinting, X chromosome inactivation, 3D chromatin architecture, local modifications of histone, and RNA polymerase II-mediated gene transcription, stands out among the diverse array of epigenetic regulators. CTCF not only functions as an architectural protein but also modulates DNA methylation and histone modifications. Epigenetic regulation of cancer has already been the focus of plenty of studies. Understanding the role of CTCF in the cancer epigenetic landscape may lead to the development of novel targeted therapeutic strategies for cancer. CTCF has already earned its status as a tumor suppressor gene by acting like a homeostatic regulator of genome integrity and function. Moreover, CTCF has a direct effect on many important transcriptional regulators that control the cell cycle, apoptosis, senescence, and differentiation. As we learn more about CTCF-mediated epigenetic modifications and transcriptional regulations, the possibility of utilizing CTCF as a diagnostic marker and therapeutic target for cancer will also increase. Thus, the current review intends to promote personalized and precision-based therapeutics for cancer patients by shedding light on the complex interplay between CTCF and epigenetic processes.
    Keywords:  CTCF; Cancer; Epigenetic regulation; Signaling pathways; Transcriptional aviator or repressor
    DOI:  https://doi.org/10.1007/s11033-023-08879-3
  4. Cell Death Discov. 2023 Oct 20. 9(1): 385
    YAP nuclear translocation induced by HIF-1α prevents DNA damage under hypoxic conditions.
    Heng-Ai Chang, Rui-Zhi Ou Yang, Jing-Ming Su, Thi My Hang Nguyen, Junne-Ming Sung, Ming-Jer Tang, Wen-Tai Chiu.
      Maladaptive repair of acute kidney injury (AKI) is associated with a high risk of developing chronic kidney disease deemed irremediable even in present days. When AKI arises from ischemia-reperfusion injury, hypoxia usually plays a major role. Although both hypoxia-inducible factor-1α (HIF-1α) and yes-associated protein (YAP) have been proven to promote renal cell survival under hypoxia, there is a lack of research that studies the crosstalk of the two and its effect on kidney repair. In studying the crosstalk, CoCl2 was used to create a mimetic hypoxic environment. Immunoprecipitation and proximity ligation assays were performed to verify protein interactions. The results show that HIF-1α interacts with YAP and promotes nuclear translocation of YAP at a high cell density under hypoxic conditions, suggesting HIF-1α serves as a direct carrier that enables YAP nuclear translocation. This is the first study to identify HIF-1α as a crucial pathway for YAP nuclear translocation under hypoxic conditions. Once translocated into a nucleus, YAP protects cells from DNA damage and apoptosis under hypoxic conditions. Since it is unlikely for YAP to translocate into a nucleus without HIF-1α, any treatment that fosters the crosstalk between the two holds the potential to improve cell recovery from hypoxic insults.
    DOI:  https://doi.org/10.1038/s41420-023-01687-5
  5. J Biomol Struct Dyn. 2023 Oct 19. 1-12
    In silico screening and identification of potential drug against p300 acetyltransferase activity in breast cancer via drug repurposing approach.
    Shilpi Sarkar, Thirukumaran Kandasamy, Rajib Shome, Siddhartha Sankar Ghosh.
      Emerging evidence portray the involvement of epigenomic reprogramming in the onset and progression of several malignancies, including breast cancer. Histone acetyltransferase (HAT) p300 is a critical epigenetic regulator that acts as a transcription co-activator and regulates various cellular processes. p300 is overexpressed in breast cancer and promotes cellular invasion and survival, making it a promising druggable target. In this study, the relevance of p300 in different cancer pathways was established. Virtual screening of the FDA-approved drug library was carried out using molecular docking, and the top 10 potential repurposed drugs were identified. Further, recalculation of binding free energy of drug-p300 complexes was carried out using molecular mechanics Poisson-Boltzmann and surface area (MM-PBSA) method after molecular dynamic simulation. Based on molecular dynamic simulation parameters and binding free energy analysis, two drugs, namely Netarsudil (-305.068 kJ/mol) and Imatinib (-260.457 kJ/mol), were identified as potential repurposed drugs to inhibit the activity of p300. In conclusion, these findings suggest, Netarsudil and Imatinib might be a potential repurposed drug to combat breast cancer via p300 inhibition.Communicated by Ramaswamy H. Sarma.
    Keywords:  Virtual screening; drug repurposing; molecular dynamics simulation; p300
    DOI:  https://doi.org/10.1080/07391102.2023.2270086
  6. PLoS Comput Biol. 2023 Oct 20. 19(10): e1011568
    Analyzing histone ChIP-seq data with a bin-based probability of being signal.
    Vivian Hecht, Kevin Dong, Sreshtaa Rajesh, Polina Shpilker, Siddarth Wekhande, Noam Shoresh.
      Histone ChIP-seq is one of the primary methods for charting the cellular epigenomic landscape, the components of which play a critical regulatory role in gene expression. Analyzing the activity of regulatory elements across datasets and cell types can be challenging due to shifting peak positions and normalization artifacts resulting from, for example, differing read depths, ChIP efficiencies, and target sizes. Moreover, broad regions of enrichment seen in repressive histone marks often evade detection by commonly used peak callers. Here, we present a simple and versatile method for identifying enriched regions in ChIP-seq data that relies on estimating a gamma distribution fit to non-overlapping 5kB genomic bins to establish a global background. We use this distribution to assign a probability of being signal (PBS) between zero and one to each 5 kB bin. This approach, while lower in resolution than typical peak-calling methods, provides a straightforward way to identify enriched regions and compare enrichments among multiple datasets, by transforming the data to values that are universally normalized and can be readily visualized and integrated with downstream analysis methods. We demonstrate applications of PBS for both broad and narrow histone marks, and provide several illustrations of biological insights which can be gleaned by integrating PBS scores with downstream data types.
    DOI:  https://doi.org/10.1371/journal.pcbi.1011568
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