bims-ectoca 2023-07-16 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023–07–16
nine papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Experimental Insights into the Interplay between Histone Modifiers and p53 in Regulating Gene Expression.
Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies.
Leveraging Gene Redundancy to Find New Histone Drivers in Cancer.
Diverse modes of regulating methyltransferase activity by histone ubiquitination.
Co-targeting autophagy and NRF2 signaling triggers mitochondrial superoxide to sensitize oral cancer stem cells for cisplatin-induced apoptosis.
Cyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesis.
Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions.
Fluorescence microscopy imaging of mitochondrial metabolism in cancer cells.
The Effects of Cetuximab and Cisplatin Anti-Cancer Drugs on the Mechanical Properties of the Lung Cancerous Cells Using Atomic Force Microscope.

Int J Mol Sci. 2023 Jul 03. pii: 11032. [Epub ahead of print]24(13):

Experimental Insights into the Interplay between Histone Modifiers and p53 in Regulating Gene Expression.

Hyun-Min Kim, Xiaoyu Zheng, Ethan Lee.

  Chromatin structure plays a fundamental role in regulating gene expression, with histone modifiers shaping the structure of chromatin by adding or removing chemical changes to histone proteins. The p53 transcription factor controls gene expression, binds target genes, and regulates their activity. While p53 has been extensively studied in cancer research, specifically in relation to fundamental cellular processes, including gene transcription, apoptosis, and cell cycle progression, its association with histone modifiers has received limited attention. This review explores the interplay between histone modifiers and p53 in regulating gene expression. We discuss how histone modifications can influence how p53 binds to target genes and how this interplay can be disrupted in cancer cells. This review provides insights into the complex mechanisms underlying gene regulation and their implications for potential cancer therapy.

Keywords:  cancer; chromatin structure; gene regulation; histone modifications; p53

DOI:  https://doi.org/10.3390/ijms241311032
MedComm (2020). 2023 Aug;4(4): e308

Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies.

Ziyu Ji, Jianlin Shen, Yujian Lan, Qian Yi, Huan Liu.

  Osteosarcoma (OS) is a highly prevalent bone malignancy among adolescents, accounting for 40% of all primary malignant bone tumors. Neoadjuvant chemotherapy combined with limb-preserving surgery has effectively reduced patient disability and mortality, but pulmonary metastases and OS cells' resistance to chemotherapeutic agents are pressing challenges in the clinical management of OS. There has been an urgent need to identify new biomarkers for OS to develop specific targeted therapies. Recently, the continued advancements in genomic analysis have contributed to the identification of clinically significant molecular biomarkers for diagnosing OS, acting as therapeutic targets, and predicting prognosis. Additionally, the contemporary molecular classifications have revealed that the signaling pathways, including Wnt/β-catenin, PI3K/AKT/mTOR, JAK/STAT3, Hippo, Notch, PD-1/PD-L1, MAPK, and NF-κB, have an integral role in OS onset, progression, metastasis, and treatment response. These molecular classifications and biological markers have created new avenues for more accurate OS diagnosis and relevant treatment. We herein present a review of the recent findings for the modulatory role of signaling pathways as possible biological markers and treatment targets for OS. This review also discusses current OS therapeutic approaches, including signaling pathway-based therapies developed over the past decade. Additionally, the review covers the signaling targets involved in the curative effects of traditional Chinese medicines in the context of expression regulation of relevant genes and proteins through the signaling pathways to inhibit OS cell growth. These findings are expected to provide directions for integrating genomic, molecular, and clinical profiles to enhance OS diagnosis and treatment.

Keywords:  clinic treatment; osteosarcoma; signaling pathway; traditional Chinese medicine

DOI:  https://doi.org/10.1002/mco2.308
Cancers (Basel). 2023 Jun 30. pii: 3437. [Epub ahead of print]15(13):

Leveraging Gene Redundancy to Find New Histone Drivers in Cancer.

Daria Ostroverkhova, Daniel Espiritu, Maria J Aristizabal, Anna R Panchenko.

  Histones play a critical role in chromatin function but are susceptible to mutagenesis. In fact, numerous mutations have been observed in several cancer types, and a few of them have been associated with carcinogenesis. Histones are peculiar, as they are encoded by a large number of genes, and the majority of them are clustered in three regions of the human genome. In addition, their replication and expression are tightly regulated in a cell. Understanding the etiology of cancer mutations in histone genes is impeded by their functional and sequence redundancy, their unusual genomic organization, and the necessity to be rapidly produced during cell division. Here, we collected a large data set of histone gene mutations in cancer and used it to investigate their distribution over 96 human histone genes and 68 different cancer types. This analysis allowed us to delineate the factors influencing the probability of mutation accumulation in histone genes and to detect new histone gene drivers. Although no significant difference in observed mutation rates between different histone types was detected for the majority of cancer types, several cancers demonstrated an excess or depletion of mutations in histone genes. As a consequence, we identified seven new histone genes as potential cancer-specific drivers. Interestingly, mutations were found to be distributed unevenly in several histone genes encoding the same protein, pointing to different factors at play, which are specific to histone function and genomic organization. Our study also elucidated mutational processes operating in genomic regions harboring histone genes, highlighting POLE as a factor of potential interest.

Keywords:  cancer driver gene; cancer mutation; chromatin; computational method; gene redundancy; histones; mutational processes; mutational signatures; nucleosome

DOI:  https://doi.org/10.3390/cancers15133437
Curr Opin Struct Biol. 2023 Jul 08. pii: S0959-440X(23)00123-9. [Epub ahead of print]82 102649

Diverse modes of regulating methyltransferase activity by histone ubiquitination.

James K Fields, Chad W Hicks, Cynthia Wolberger.

Post-translational modification of histones plays a central role in regulating transcription. Methylation of histone H3 at lysines 4 (H3K4) and 79 (H3K79) play roles in activating transcription whereas methylation of H3K27 is a repressive mark. These modifications, in turn, depend upon prior monoubiquitination of specific histone residues in a phenomenon known as histone crosstalk. Earlier work had provided insights into the mechanism by which monoubiquitination histone H2BK120 stimulates H3K4 methylation by COMPASS/MLL1 and H3K79 methylation by DOT1L, and monoubiquitinated H2AK119 stimulates methylation of H3K27 by the PRC2 complex. Recent studies have shed new light on the role of individual subunits and paralogs in regulating the activity of PRC2 and how additional post-translational modifications regulate yeast Dot1 and human DOT1L, as well as provided new insights into the regulation of MLL1 by H2BK120ub.

DOI: https://doi.org/10.1016/j.sbi.2023.102649
Free Radic Biol Med. 2023 Jul 07. pii: S0891-5849(23)00526-9. [Epub ahead of print]

Co-targeting autophagy and NRF2 signaling triggers mitochondrial superoxide to sensitize oral cancer stem cells for cisplatin-induced apoptosis.

Prakash P Praharaj, Amruta Singh, Srimanta Patra, Sujit K Bhutia.

  Cancer stem cell (CSC) populations are regulated by autophagy, which in turn modulates tumorigenicity and malignancy. In this study, we demonstrate that cisplatin treatment enriches the CSCs population by increasing autophagosome formation and speeding up autophagosome-lysosome fusion by recruiting RAB7 to autolysosomes. Further, cisplatin treatment stimulates lysosomal activity and increases autophagic flux in oral CD44+ cells. Interestingly, both ATG5-and BECN1-dependent autophagy are essential for maintaining cancer stemness, self-renewal, and resistance to cisplatin-induced cytotoxicity in oral CD44+ cells. Moreover, we discovered that autophagy-deficient (shATG5 and/or shBECN1) CD44+ cells benefited from cisplatin treatment because it activated NRF2 (nuclear factor, erythroid 2 like 2) signaling, which in turn reduces the elevated ROS level enhancing cancer stemness. Genetic inhibition of NRF2 (siNRF2) in autophagy-deficient CD44+ cells increases mtROS level, reducing cisplatin-resistance CSCs, and pre-treatment with mitoTEMPO [a mitochondria-targeted SOD (superoxide dismutase) mimetic] lessened the cytotoxic effect enhancing cancer stemness. We also found that inhibiting autophagy (with CQ) and NRF2 signaling (with ML-385) combinedly increased cisplatin cytotoxicity, thereby suppressing the expansion of oral CD44+ cells; this finding has the potential to be clinically applicable in resolving CSC-associated chemoresistance and tumor relapse in oral cancer.

Keywords:  Apoptosis; Autophagy; Cancer stem cell; NRF2; Oral cancer; mtROS

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.07.008
Cell Rep. 2023 Jul 09. pii: S2211-1247(23)00779-9. [Epub ahead of print]42(7): 112768

Cyclin E/CDK2 and feedback from soluble histone protein regulate the S phase burst of histone biosynthesis.

Claire Armstrong, Victor J Passanisi, Humza M Ashraf, Sabrina L Spencer.

  Faithful DNA replication requires that cells fine-tune their histone pool in coordination with cell-cycle progression. Replication-dependent histone biosynthesis is initiated at a low level upon cell-cycle commitment, followed by a burst at the G1/S transition, but it remains unclear how exactly the cell regulates this burst in histone biosynthesis as DNA replication begins. Here, we use single-cell time-lapse imaging to elucidate the mechanisms by which cells modulate histone production during different phases of the cell cycle. We find that CDK2-mediated phosphorylation of NPAT at the restriction point triggers histone transcription, which results in a burst of histone mRNA precisely at the G1/S phase boundary. Excess soluble histone protein further modulates histone abundance by promoting the degradation of histone mRNA for the duration of S phase. Thus, cells regulate their histone production in strict coordination with cell-cycle progression by two distinct mechanisms acting in concert.

Keywords:  3′hExo; CDK2; CP: Cell biology; CP: Molecular biology; FLASH; Lsm11; NASP; NPAT; SLBP; histone locus body; replication-dependent histone; restriction point

DOI:  https://doi.org/10.1016/j.celrep.2023.112768
Cancers (Basel). 2023 Jul 05. pii: 3506. [Epub ahead of print]15(13):

Targeting Transcription Factor YY1 for Cancer Treatment: Current Strategies and Future Directions.

Rendy Hosea, Sharon Hillary, Shourong Wu, Vivi Kasim.

  Cancer represents a significant and persistent global health burden, with its impact underscored by its prevalence and devastating consequences. Whereas numerous oncogenes could contribute to cancer development, a group of transcription factors (TFs) are overactive in the majority of tumors. Targeting these TFs may also combat the downstream oncogenes activated by the TFs, making them attractive potential targets for effective antitumor therapeutic strategy. One such TF is yin yang 1 (YY1), which plays crucial roles in the development and progression of various tumors. In preclinical studies, YY1 inhibition has shown efficacy in inhibiting tumor growth, promoting apoptosis, and sensitizing tumor cells to chemotherapy. Recent studies have also revealed the potential of combining YY1 inhibition with immunotherapy for enhanced antitumor effects. However, clinical translation of YY1-targeted therapy still faces challenges in drug specificity and delivery. This review provides an overview of YY1 biology, its role in tumor development and progression, as well as the strategies explored for YY1-targeted therapy, with a focus on their clinical implications, including those using small molecule inhibitors, RNA interference, and gene editing techniques. Finally, we discuss the challenges and current limitations of targeting YY1 and the need for further research in this area.

Keywords:  YY1-targeted therapy; antitumor therapy; clinical implications; drug resistance; yin yang 1 (YY1)

DOI:  https://doi.org/10.3390/cancers15133506
Front Oncol. 2023 ;13 1152553

Fluorescence microscopy imaging of mitochondrial metabolism in cancer cells.

Monika Gooz, Eduardo N Maldonado.

  Mitochondrial metabolism is an important contributor to cancer cell survival and proliferation that coexists with enhanced glycolytic activity. Measuring mitochondrial activity is useful to characterize cancer metabolism patterns, to identify metabolic vulnerabilities and to identify new drug targets. Optical imaging, especially fluorescent microscopy, is one of the most valuable tools for studying mitochondrial bioenergetics because it provides semiquantitative and quantitative readouts as well as spatiotemporal resolution of mitochondrial metabolism. This review aims to acquaint the reader with microscopy imaging techniques currently used to determine mitochondrial membrane potential (ΔΨm), nicotinamide adenine dinucleotide (NADH), ATP and reactive oxygen species (ROS) that are major readouts of mitochondrial metabolism. We describe features, advantages, and limitations of the most used fluorescence imaging modalities: widefield, confocal and multiphoton microscopy, and fluorescent lifetime imaging (FLIM). We also discus relevant aspects of image processing. We briefly describe the role and production of NADH, NADHP, flavins and various ROS including superoxide and hydrogen peroxide and discuss how these parameters can be analyzed by fluorescent microscopy. We also explain the importance, value, and limitations of label-free autofluorescence imaging of NAD(P)H and FAD. Practical hints for the use of fluorescent probes and newly developed sensors for imaging ΔΨm, ATP and ROS are described. Overall, we provide updated information about the use of microscopy to study cancer metabolism that will be of interest to all investigators regardless of their level of expertise in the field.

Keywords:  FAD; NAD(P)H; ROS; fluorescence microscopy; mitochondrial membrane potential; mitochondrial metabolism

DOI:  https://doi.org/10.3389/fonc.2023.1152553
Biochem Cell Biol. 2023 Jul 12.

The Effects of Cetuximab and Cisplatin Anti-Cancer Drugs on the Mechanical Properties of the Lung Cancerous Cells Using Atomic Force Microscope.

Iraj Rezaei, Ali Sadeghi.

Each anti-cancer drug has special effects on the target cells. One of the most important reasons to recommend an anti-cancer drug is related to the influences of it on the mechanical properties of the target cells. In this study, the effect of Cetuximab and Cisplatin anti-cancer drugs on the mechanical properties of A-549 and Calu-6 cells as the cancerous lung cells have been investigated. The mechanical specifications of the cells before and after treatment were obtained using nanoindentation by the JPK Instruments' NanoWizard3 atomic force microscope (AFM). The results show that Cetuximab increases the stiffness of A-549 cell from 1225 Pa to 3403 Pa and 12690 Pa for 24 and 48h incubations. The influence of Cetuximab on the of Calu-6 shows that the elastic modulus after 24 and 48h culture times increases about Cisplatin anti-cancer drug for A-549 cell indicates that the elastic modulus raises from 1225 Pa to 1506 Pa and 2375 Pa for 24 and 48h respectively. For Calu-6 cell, Cisplatin has an important role to increase the stiffness of the cell. Applying Cisplatin increases the elastic modulus from 33 Pa to 682.8 Pa for 24h and 1105 Pa after 48h incubations.

DOI: https://doi.org/10.1139/bcb-2022-0322