bims-ectoca 2022-10-23 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022–10–23
nine papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities.
Evaluation of Small-Molecule HDAC Inhibitors Through In Vitro and In Cellulo Approaches.
Advances of targeting the YAP/TAZ-TEAD complex in the hippo pathway for the treatment of cancers.
Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury.
Interpretable deep learning for chromatin-informed inference of transcriptional programs driven by somatic alterations across cancers.
Targeting Transcription Factors in Cancer: From "Undruggable" to "Druggable".
The distinguishing electrical properties of cancer cells.
CREAMMIST: an integrative probabilistic database for cancer drug response prediction.
YAP, a novel target regulates F-actin rearrangement-associated CAFs transformation and promotes colorectal cancer cell progression.

Cancer Commun (Lond). 2022 Oct 20.

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities.

Tongxin Ge, Xiang Gu, Renbing Jia, Shengfang Ge, Peiwei Chai, Ai Zhuang, Xianqun Fan.

  Reversible, spatial, and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis. Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation. Epigenetic dysregulation is a common feature of human cancers, which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression. The epigenome is sensitive to metabolic changes. Metabolism produces various metabolites that are substrates, cofactors, or inhibitors of epigenetic enzymes. Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epigenetic landscape, inducing transcriptional responses to heterogeneous metabolic requirements. Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post-transcriptional levels. Epigenetic modifiers, chromatin remodelers and non-coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism, facilitating malignant transformation. However, the significance of the close connection between metabolism and epigenetics in the context of cancer has not been fully deciphered. Thus, it will be constructive to summarize and update the emerging new evidence supporting this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options. In this review, we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aberrations and metabolic rewiring to cancer initiation and development. Finally, we highlight the potential therapeutic opportunities for hematological malignancies and solid tumors by targeting this epigenetic-metabolic circuit. In summary, we endeavored to depict the current understanding of the coordination between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.

Keywords:  RNA epigenetics; cancer; epigenetics; metabolic reprogramming; therapy

DOI:  https://doi.org/10.1002/cac2.12374
Methods Mol Biol. 2023 ;2589 157-177

Evaluation of Small-Molecule HDAC Inhibitors Through In Vitro and In Cellulo Approaches.

Nabanita Nawar, Harsimran Kaur Garcha, Abootaleb Sedighi, Elvin D de Araujo, Patrick T Gunning.

  The aberrant activity of histone deacetylases (HDACs) across a broad range of cancers and other disease indications has led to the development of small-molecule inhibitors that target one or more members of the HDAC protein family. Emerging HDAC inhibitors that show promise in drug discovery programs must be assessed across a range of in vitro assays to establish an inhibitor profile for potency and cellular selectivity towards target HDAC(s) as well as preliminary absorption, distribution, metabolism, and excretion (ADME) features. Here we provide an overview of methods to determine a subset of pivotal in vitro drug-like parameters for HDAC inhibitors (HDACi). We initially describe protocols for parallel artificial membrane permeability assays (PAMPA) to evaluate the passive permeability of small molecules across lipid membranes. Subsequently, we elaborate on cytotoxicity assays using CellTiter-Blue to determine HDACi-induced cell death in healthy/diseased cellular models. We next focus on assessing the target engagement of inhibitors with the appropriate HDAC isoforms in a cellular environment via Western blotting of acetylated HDAC substrates. Finally, we provide detailed guidelines on how to assess the metabolic stability of HDACi through whole blood stability assays. Collectively, these assays provide an overview of the permeability, selectivity, and stability of the HDAC inhibitor under development.

Keywords:  Cytotoxicity; HDAC inhibitor; PAMPA; Selectivity; Stability; Western blotting; Whole blood

DOI:  https://doi.org/10.1007/978-1-0716-2788-4_11
Eur J Med Chem. 2022 Oct 13. pii: S0223-5234(22)00749-8. [Epub ahead of print]244 114847

Advances of targeting the YAP/TAZ-TEAD complex in the hippo pathway for the treatment of cancers.

Mengxin Luo, Yongjin Xu, Haifeng Chen, Yiquan Wu, Ao Pang, Junjie Hu, Xiaowu Dong, Jinxin Che, Haiyan Yang.

  The Hippo pathway is an evolutionarily conserved signaling pathway that plays critical roles in the tumorigenesis and progression of breast cancer, oral cancer, rectal cancer, colloid cancer, and so on. YAP/TAZ-TEAD complex is a key knot in the Hippo pathway regulating cell proliferation and stem cell functions. Activation or overexpression of this complex has been proved to lead to cell transformation, proliferation and eventually cancerization. In this review, the association between the alterations of hippo pathway and tumorigenesis of various cancer had been elucidated. The structural basis of YAP/TAZ-TEAD complex is analyzed, and the targeting inhibitors are summarized within the medicinal chemistry classification. Moreover, we have also discussed the clinical status and current challenges of these drug candidates, and provide guidance for the future development of inhibitors targeting this pathway, especially YAP/TAZ-TEAD complex.

Keywords:  Cancers; Hippo pathway; Palmitoyl pocket; Targeting inhibitors; YAP/TAZ-TEAD complex

DOI:  https://doi.org/10.1016/j.ejmech.2022.114847
Elife. 2022 Oct 18. pii: e78540. [Epub ahead of print]11

Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury.

Lilija Wehling, Liam Keegan, Paula Fernández-Palanca, Reham Hassan, Ahmed Ghallab, Jennifer Schmitt, Yingyue Tang, Maxime Le Marois, Stephanie Roessler, Peter Schirmacher, Ursula Kummer, Jan G Hengstler, Sven Sahle, Kai Breuhahn.

  The Hippo signaling pathway controls cell proliferation and tissue regeneration via its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). The canonical pathway topology is characterized by sequential phosphorylation of kinases in the cytoplasm that defines the subcellular localization of YAP and TAZ. However, the molecular mechanisms controlling the nuclear/cytoplasmic shuttling dynamics of both factors under physiological and tissue-damaging conditions are poorly understood. By implementing experimental in vitro data, partial differential equation modeling, as well as automated image analysis, we demonstrate that nuclear phosphorylation contributes to differences between YAP and TAZ localization in the nucleus and cytoplasm. Treatment of hepatocyte-derived cells with hepatotoxic acetaminophen (APAP) induces a biphasic protein phosphorylation eventually leading to nuclear protein enrichment of YAP but not TAZ. APAP-dependent regulation of nuclear/cytoplasmic YAP shuttling is not an unspecific cellular response but relies on the sequential induction of reactive oxygen species (ROS), RAC-alpha serine/threonine-protein kinase (AKT, synonym: protein kinase B), as well as elevated nuclear interaction between YAP and AKT. Mouse experiments confirm this sequence of events illustrated by the expression of ROS-, AKT-, and YAP-specific gene signatures upon APAP administration. In summary, our data illustrate the importance of nuclear processes in the regulation of Hippo pathway activity. YAP and TAZ exhibit different shuttling dynamics, which explains distinct cellular responses of both factors under physiological and tissue-damaging conditions.

Keywords:  DILI; Hippo pathway; TAZ; acetaminophen; computational biology; human; medicine; mouse; partial differential equations; systems biology

DOI:  https://doi.org/10.7554/eLife.78540
Nucleic Acids Res. 2022 Oct 16. pii: gkac881. [Epub ahead of print]

Interpretable deep learning for chromatin-informed inference of transcriptional programs driven by somatic alterations across cancers.

Yifeng Tao, Xiaojun Ma, Drake Palmer, Russell Schwartz, Xinghua Lu, Hatice Ulku Osmanbeyoglu.

Cancer is a disease of gene dysregulation, where cells acquire somatic and epigenetic alterations that drive aberrant cellular signaling. These alterations adversely impact transcriptional programs and cause profound changes in gene expression. Interpreting somatic alterations within context-specific transcriptional programs will facilitate personalized therapeutic decisions but is a monumental task. Toward this goal, we develop a partially interpretable neural network model called Chromatin-informed Inference of Transcriptional Regulators Using Self-attention mechanism (CITRUS). CITRUS models the impact of somatic alterations on transcription factors and downstream transcriptional programs. Our approach employs a self-attention mechanism to model the contextual impact of somatic alterations. Furthermore, CITRUS uses a layer of hidden nodes to explicitly represent the state of transcription factors (TFs) to learn the relationships between TFs and their target genes based on TF binding motifs in the open chromatin regions of tumor samples. We apply CITRUS to genomic, transcriptomic, and epigenomic data from 17 cancer types profiled by The Cancer Genome Atlas. CITRUS predicts patient-specific TF activities and reveals transcriptional program variations between and within tumor types. We show that CITRUS yields biological insights into delineating TFs associated with somatic alterations in individual tumors. Thus, CITRUS is a promising tool for precision oncology.

DOI: https://doi.org/10.1093/nar/gkac881
Methods Mol Biol. 2023 ;2594 107-131

Targeting Transcription Factors in Cancer: From "Undruggable" to "Druggable".

Zhipeng Tao, Xu Wu.

  Deregulation of transcription factors is critical to hallmarks of cancer. Genetic mutations, gene fusions, amplifications or deletions, epigenetic alternations, and aberrant post-transcriptional modification of transcription factors are involved in the regulation of various stages of carcinogenesis, including cancer initiation, progression, and metastasis. Thus, targeting the dysfunctional transcription factors may lead to new cancer therapeutic strategies. However, transcription factors are conventionally considered as "undruggable." Here, we summarize the recent progresses in understanding the regulation of transcription factors in cancers and strategies to target transcription factors and co-factors for preclinical and clinical drug development, particularly focusing on c-Myc, YAP/TAZ, and β-catenin due to their significance and interplays in cancer.

Keywords:  Cancer; Druggable; Transcription co-factors; Transcription factor; Undruggable

DOI:  https://doi.org/10.1007/978-1-0716-2815-7_9
Phys Life Rev. 2022 Oct 04. pii: S1571-0645(22)00063-X. [Epub ahead of print]43 139-188

The distinguishing electrical properties of cancer cells.

Elisabetta Di Gregorio, Simone Israel, Michael Staelens, Gabriella Tankel, Karthik Shankar, Jack A Tuszyński.

  In recent decades, medical research has been primarily focused on the inherited aspect of cancers, despite the reality that only 5-10% of tumours discovered are derived from genetic causes. Cancer is a broad term, and therefore it is inaccurate to address it as a purely genetic disease. Understanding cancer cells' behaviour is the first step in countering them. Behind the scenes, there is a complicated network of environmental factors, DNA errors, metabolic shifts, and electrostatic alterations that build over time and lead to the illness's development. This latter aspect has been analyzed in previous studies, but how the different electrical changes integrate and affect each other is rarely examined. Every cell in the human body possesses electrical properties that are essential for proper behaviour both within and outside of the cell itself. It is not yet clear whether these changes correlate with cell mutation in cancer cells, or only with their subsequent development. Either way, these aspects merit further investigation, especially with regards to their causes and consequences. Trying to block changes at various levels of occurrence or assisting in their prevention could be the key to stopping cells from becoming cancerous. Therefore, a comprehensive understanding of the current knowledge regarding the electrical landscape of cells is much needed. We review four essential electrical characteristics of cells, providing a deep understanding of the electrostatic changes in cancer cells compared to their normal counterparts. In particular, we provide an overview of intracellular and extracellular pH modifications, differences in ionic concentrations in the cytoplasm, transmembrane potential variations, and changes within mitochondria. New therapies targeting or exploiting the electrical properties of cells are developed and tested every year, such as pH-dependent carriers and tumour-treating fields. A brief section regarding the state-of-the-art of these therapies can be found at the end of this review. Finally, we highlight how these alterations integrate and potentially yield indications of cells' malignancy or metastatic index.

Keywords:  Electromagnetic fields; Electrophysiology; Ion channel expression; Ionic conductivity; Mitochondrial membrane potential; Oncology

DOI:  https://doi.org/10.1016/j.plrev.2022.09.003
Nucleic Acids Res. 2022 Oct 19. pii: gkac911. [Epub ahead of print]

CREAMMIST: an integrative probabilistic database for cancer drug response prediction.

Hatairat Yingtaweesittikul, Jiaxi Wu, Aanchal Mongia, Rafael Peres, Karrie Ko, Niranjan Nagarajan, Chayaporn Suphavilai.

Extensive in vitro cancer drug screening datasets have enabled scientists to identify biomarkers and develop machine learning models for predicting drug sensitivity. While most advancements have focused on omics profiles, cancer drug sensitivity scores precalculated by the original sources are often used as-is, without consideration for variabilities between studies. It is well-known that significant inconsistencies exist between the drug sensitivity scores across datasets due to differences in experimental setups and preprocessing methods used to obtain the sensitivity scores. As a result, many studies opt to focus only on a single dataset, leading to underutilization of available data and a limited interpretation of cancer pharmacogenomics analysis. To overcome these caveats, we have developed CREAMMIST (https://creammist.mtms.dev), an integrative database that enables users to obtain an integrative dose-response curve, to capture uncertainty (or high certainty when multiple datasets well align) across five widely used cancer cell-line drug-response datasets. We utilized the Bayesian framework to systematically integrate all available dose-response values across datasets (>14 millions dose-response data points). CREAMMIST provides easy-to-use statistics derived from the integrative dose-response curves for various downstream analyses such as identifying biomarkers, selecting drug concentrations for experiments, and training robust machine learning models.

DOI: https://doi.org/10.1093/nar/gkac911
Biomed Pharmacother. 2022 Nov;pii: S0753-3322(22)01146-5. [Epub ahead of print]155 113757

YAP, a novel target regulates F-actin rearrangement-associated CAFs transformation and promotes colorectal cancer cell progression.

Chonnapat Naktubtim, Witchuda Payuhakrit, Tamonwan Uttarawichien, Artchaya Hassametto, Prasit Suwannalert.

  Colorectal cancer (CRC) progression is strongly influenced by the tumor microenvironment (TME) in which cancer-associated fibroblasts (CAFs) are the major components influencing CRC growth and progression. The present study aimed to investigate the effect of YAP on F-actin arrangement in CAF transformation and the possibility of using YAP as a target for inhibiting CRC growth and progression. Conditioned media were collected from direct interaction between CRC cells and fibroblasts. CAF markers were investigated by flow cytometry, western blot analysis, and immunofluorescence assay in CM-treated fibroblasts. Promoting the CRC progression of conditioned media was determined in CRC cells by using MTT assay, fluorescence assay, wound healing assay, transwell migration assay, and tubulogenesis. The results showed that the conditioned media induced the expression of CAF markers associated with the central rearrangement of F-actin in colon fibroblasts, upregulating and promoting the nuclear translocation of YAP. The conditioned media also significantly promoted the proliferation, migration, invasion, and angiogenesis of CRC cells. Interestingly, Verteporfin, a YAP inhibitor during cocultivation, abolished the conversion of CAFs and inhibited proliferation, migration, invasion, and angiogenesis in CRC cells. Moreover, bioinformatics analysis was employed to determine the potential role of YAP as a prognostic marker in CRC patients from databases. The results suggested that YAP has higher expression in CRC patients and is associated with a poor prognosis. In conclusion, these findings demonstrate that YAP-related F-actin rearrangement may be a potential new target of combination therapy with a focus on targeting TME.

Keywords:  Cancer progression; Cancer-associated fibroblast; Colorectal cancer; F-actin; YAP

DOI:  https://doi.org/10.1016/j.biopha.2022.113757