bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2024–01–28
nine papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. The LKB1-TSSK1B axis controls YAP phosphorylation to regulate the Hippo-YAP pathway.
  2. Viable tumor cell density after neoadjuvant chemotherapy assessed using deep learning model reflects the prognosis of osteosarcoma.
  3. Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness.
  4. YAP mechanotransduction under cyclic mechanical stretch loading for mesenchymal stem cell osteogenesis is regulated by ROCK.
  5. Single cell proteomics by mass spectrometry reveals deep epigenetic insight and new targets of a class specific histone deacetylase inhibitor.
  6. YAP1 expression in colorectal cancer confers the aggressive phenotypes via its target genes.
  7. Prognostic and predictive value of super-enhancer-derived signatures for survival and lung metastasis in osteosarcoma.
  8. Role of Epigenetics for the Efficacy of Cisplatin.
  9. A Two-Step Mechanism for Creating Stable, Condensed Chromatin with the Polycomb Complex PRC1.
  1. Cell Death Dis. 2024 01 20. 15(1): 76
    The LKB1-TSSK1B axis controls YAP phosphorylation to regulate the Hippo-YAP pathway.
    Cho-Long Kim, Su-Bin Lim, Sue-Hee Choi, Dong Hyun Kim, Ye Eun Sim, Eun-Hye Jo, Keeeun Kim, Keesook Lee, Hee-Sae Park, Su Bin Lim, Li-Jung Kang, Han-Sol Jeong, Youngsoo Lee, Carsten G Hansen, Jung-Soon Mo.
      The Hippo pathway's main effector, Yes-associated protein (YAP), plays a crucial role in tumorigenesis as a transcriptional coactivator. YAP's phosphorylation by core upstream components of the Hippo pathway, such as mammalian Ste20 kinase 1/2 (MST1/2), mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), and their substrate, large tumor suppressor 1/2 (LATS1/2), influences YAP's subcellular localization, stability, and transcriptional activity. However, recent research suggests the existence of alternative pathways that phosphorylate YAP, independent of these core upstream Hippo pathway components, raising questions about additional means to inactivate YAP. In this study, we present evidence demonstrating that TSSK1B, a calcium/calmodulin-dependent protein kinase (CAMK) superfamily member, is a negative regulator of YAP, suppressing cellular proliferation and oncogenic transformation. Mechanistically, TSSK1B inhibits YAP through two distinct pathways. Firstly, the LKB1-TSSK1B axis directly phosphorylates YAP at Ser94, inhibiting the YAP-TEAD complex's formation and suppressing its target genes' expression. Secondly, the TSSK1B-LATS1/2 axis inhibits YAP via phosphorylation at Ser127. Our findings reveal the involvement of TSSK1B-mediated molecular mechanisms in the Hippo-YAP pathway, emphasizing the importance of multilevel regulation in critical cellular decision-making processes.
    DOI:  https://doi.org/10.1038/s41419-024-06465-4
  2. NPJ Precis Oncol. 2024 Jan 22. 8(1): 16
    Viable tumor cell density after neoadjuvant chemotherapy assessed using deep learning model reflects the prognosis of osteosarcoma.
    Kengo Kawaguchi, Kazuki Miyama, Makoto Endo, Ryoma Bise, Kenichi Kohashi, Takeshi Hirose, Akira Nabeshima, Toshifumi Fujiwara, Yoshihiro Matsumoto, Yoshinao Oda, Yasuharu Nakashima.
      Prognosis after neoadjuvant chemotherapy (NAC) for osteosarcoma is generally predicted using manual necrosis-rate assessments; however, necrosis rates obtained in these assessments are not reproducible and do not adequately reflect individual cell responses. We aimed to investigate whether viable tumor cell density assessed using a deep-learning model (DLM) reflects the prognosis of osteosarcoma. Seventy-one patients were included in this study. Initially, the DLM was trained to detect viable tumor cells, following which it calculated their density. Patients were stratified into high and low-viable tumor cell density groups based on DLM measurements, and survival analysis was performed to evaluate disease-specific survival and metastasis-free survival (DSS and MFS). The high viable tumor cell density group exhibited worse DSS (p = 0.023) and MFS (p = 0.033). DLM-evaluated viable density showed correct stratification of prognosis groups. Therefore, this evaluation method may enable precise stratification of the prognosis in osteosarcoma patients treated with NAC.
    DOI:  https://doi.org/10.1038/s41698-024-00515-y
  3. bioRxiv. 2024 Jan 10. pii: 2024.01.10.574997. [Epub ahead of print]
    Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness.
    Brian D Cosgrove, Lexi R Bounds, Carson Key Taylor, Alan L Su, Anthony J Rizzo, Alejandro Barrera, Gregory E Crawford, Brenton D Hoffman, Charles A Gersbach.
      Epigenetic control of cellular transcription and phenotype is influenced by changes in the cellular microenvironment, yet how mechanical cues from these microenvironments precisely influence epigenetic state to regulate transcription remains largely unmapped. Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq CRISPR screening to identify a new class of genomic enhancers that responds to the mechanical microenvironment. These 'mechanoenhancers' could be active on either soft or stiff extracellular matrix contexts, and regulated transcription to influence critical cell functions including apoptosis, mechanotransduction, proliferation, and migration. Epigenetic editing of mechanoenhancers on rigid materials tuned gene expression to levels observed on softer materials, thereby reprogramming the cellular response to the mechanical microenvironment. These editing approaches may enable the precise alteration of mechanically-driven disease states.
    DOI:  https://doi.org/10.1101/2024.01.10.574997
  4. Front Bioeng Biotechnol. 2023 ;11 1306002
    YAP mechanotransduction under cyclic mechanical stretch loading for mesenchymal stem cell osteogenesis is regulated by ROCK.
    Eunju Kim, Brandon D Riehl, Tasneem Bouzid, Ruiguo Yang, Bin Duan, Henry J Donahue, Jung Yul Lim.
      While yes-associated protein (YAP) is now recognized as a potent mechanosensitive transcriptional regulator to affect cell growth and differentiation including the osteogenic transcription of mesenchymal stem cells (MSCs), most studies have reported the YAP mechanosensing of static mechanophysical cues such as substrate stiffness. We tested MSC response to dynamic loading, i.e., cyclic mechanical stretching, and assessed YAP mechanosensing and resultant MSC osteogenesis. We showed that cyclic stretching at 10% strain and 1 Hz frequency triggered YAP nuclear import in MSCs. YAP phosphorylation at S127 and S397, which is required for YAP cytoplasmic retention, was suppressed by cyclic stretch. We also observed that anti-YAP-regulatory Hippo pathway, LATS phosphorylation, was significantly decreased by stretch. We confirmed the stretch induction of MSC osteogenic transcription and differentiation, and this was impaired under YAP siRNA suggesting a key role of YAP dynamic mechanosensing in MSC osteogenesis. As an underlying mechanism, we showed that the YAP nuclear transport by cyclic stretch was abrogated by ROCK inhibitor, Y27632. ROCK inhibitor also impaired the stretch induction of F-actin formation and MSC osteogenesis, thus implicating the role of the ROCK-F-actin cascade in stretch-YAP dynamic mechanosensing-MSC osteogenesis. Our results provide insight into bone tissue engineering and skeletal regenerative capacity of MSCs especially as regards the role of dynamic mechanical loading control of YAP-mediated MSC osteogenic transcription.
    Keywords:  Hippo; ROCK; YAP; mechanical stretch loading; mesenchymal stem cell; osteogenesis
    DOI:  https://doi.org/10.3389/fbioe.2023.1306002
  5. bioRxiv. 2024 Jan 06. pii: 2024.01.05.574437. [Epub ahead of print]
    Single cell proteomics by mass spectrometry reveals deep epigenetic insight and new targets of a class specific histone deacetylase inhibitor.
    Benjamin C Orsburn.
      Epigenetic programming has been shown to play a role in nearly every human system and disease where anyone has thought to look. However, the levels of heterogeneity at which epigenetic or epiproteomic modifications occur at single cell resolution across a population remains elusive. While recent advances in sequencing technology have allowed between 1 and 3 histone post-translational modifications to be analyzed in each single cell, over twenty separate chemical PTMs are known to exist, allowing thousands of possible combinations. Single cell proteomics by mass spectrometry (SCP) is an emerging technology in which hundreds or thousands of proteins can be directly quantified in typical human cells. As the proteins detected and quantified by SCP are heavily biased toward proteins of highest abundance, chromatin proteins are an attractive target for analysis. To this end, I applied SCP to the analysis of cancer cells treated with mocetinostat, a class specific histone deacetylase inhibitor. I find that 16 PTMs can be confidently identified and localized with high site specificity in single cells. In addition, the high abundance of histone proteins allows higher throughput methods to be utilized for SCP than ever described. While quantitative accuracy suffers when analyzing more than 700 cells per day, 9 histone proteins can be measured in single cells analyzed at even 3,500 cells per day, a throughput 10-fold greater than any previous report. In addition, the unbiased global approach utilized herein identifies a previously uncharacterized response to this drug through the S100-A8/S100-A9 protein complex partners. This response is observed in nearly every cell of the over 1,000 analyzed in this study, regardless of the relative throughput of the method utilized. While limitations exist in the methods described herein, current technologies can easily improve upon the results presented here to allow comprehensive analysis of histone PTMs to be performed in any mass spectrometry lab. All raw and processed data described in this study has been made publicly available through the ProteomeXchange/MASSIVE repository system as MSV000093434.
    Abstract graphic:
    DOI:  https://doi.org/10.1101/2024.01.05.574437
  6. Cell Cycle. 2024 Jan 23. 1-9
    YAP1 expression in colorectal cancer confers the aggressive phenotypes via its target genes.
    Haoyuan Chen, Yangyang Shang, Xia Li, Rongquan Wang.
      Yes-associated protein1 (YAP1), a downstream effector of the Hippo pathway, is over-expressed in several types of malignancies. We analyzed retrospectively the TCGA database using 447 colorectal cancer (CRC) samples to determine the correlation between YAP1 expression level and CRC patient prognosis. YAP1-enforced expressed CRC cell lines were constructed using the lentivirus particles containing a YAP1 insert. YAP1 was highly expressed in CRC cancerous tissues and is associated with distant metastasis of CRC patients. Kaplan - Meier analysis indicated that CRC patients with a higher YAP1 expression group (n = 104) had worse disease-free survival (DFS) and overall survival (OS) than lower YAP1 expression group (n = 343) (p = 0.008 and p = 0.022). Univariate and multivariate analysis indicated that the elevated YAP1 expression predicted the aggressive phenotype and was an independent indicator for OS and DFS of CRC patients. YAP1 over-expression in CRC cells enhanced their migration and invasion significantly which can be reversed by AXL, CTGF, or CYR61 interference. The study suggested that YAP1 affected the prognosis of CRC patients and controlled the abilities of invasion and migration of CRC cells via its target genes AXL, CTGF, and CYR61.
    Keywords:  YAP1; colorectal cancer; hippo signaling; migration; prognosis; survival
    DOI:  https://doi.org/10.1080/15384101.2024.2309017
  7. J Transl Med. 2024 Jan 22. 22(1): 88
    Prognostic and predictive value of super-enhancer-derived signatures for survival and lung metastasis in osteosarcoma.
    Guanyu Huang, Xuelin Zhang, Yu Xu, Shuo Chen, Qinghua Cao, Weihai Liu, Yiwei Fu, Qiang Jia, Jingnan Shen, Junqiang Yin, Jiajun Zhang.
       BACKGROUND: Risk stratification and personalized care are crucial in managing osteosarcoma due to its complexity and heterogeneity. However, current prognostic prediction using clinical variables has limited accuracy. Thus, this study aimed to explore potential molecular biomarkers to improve prognostic assessment.
    METHODS: High-throughput inhibitor screening of 150 compounds with broad targeting properties was performed and indicated a direction towards super-enhancers (SEs). Bulk RNA-seq, scRNA-seq, and immunohistochemistry (IHC) were used to investigate SE-associated gene expression profiles in osteosarcoma cells and patient tissue specimens. Data of 212 osteosarcoma patients who received standard treatment were collected and randomized into training and validation groups for retrospective analysis. Prognostic signatures and nomograms for overall survival (OS) and lung metastasis-free survival (LMFS) were developed using Cox regression analyses. The discriminatory power, calibration, and clinical value of nomograms were evaluated.
    RESULTS: High-throughput inhibitor screening showed that SEs significantly contribute to the oncogenic transcriptional output in osteosarcoma. Based on this finding, focus was given to 10 SE-associated genes with distinct characteristics and potential oncogenic function. With multi-omics approaches, the hyperexpression of these genes was observed in tumor cell subclusters of patient specimens, which were consistently correlated with poor outcomes and rapid metastasis, and the majority of these identified SE-associated genes were confirmed as independent risk factors for poor outcomes. Two molecular signatures were then developed to predict survival and occurrence of lung metastasis: the SE-derived OS-signature (comprising LACTB, CEP55, SRSF3, TCF7L2, and FOXP1) and the SE-derived LMFS-signature (comprising SRSF3, TCF7L2, FOXP1, and APOLD1). Both signatures significantly improved prognostic accuracy beyond conventional clinical factors.
    CONCLUSIONS: Oncogenic transcription driven by SEs exhibit strong associations with osteosarcoma outcomes. The SE-derived signatures developed in this study hold promise as prognostic biomarkers for predicting OS and LMFS in patients undergoing standard treatments. Integrative prognostic models that combine conventional clinical factors with these SE-derived signatures demonstrate substantially improved accuracy, and have the potential to facilitate patient counseling and individualized management.
    Keywords:  Lung metastasis; Osteosarcoma; Prognostic signature; Super-enhancer; Survival
    DOI:  https://doi.org/10.1186/s12967-024-04902-8
  8. Int J Mol Sci. 2024 Jan 17. pii: 1130. [Epub ahead of print]25(2):
    Role of Epigenetics for the Efficacy of Cisplatin.
    Tatjana Lumpp, Sandra Stößer, Franziska Fischer, Andrea Hartwig, Beate Köberle.
      The clinical utility of the chemotherapeutic agent cisplatin is restricted by cancer drug resistance, which is either intrinsic to the tumor or acquired during therapy. Epigenetics is increasingly recognized as a factor contributing to cisplatin resistance and hence influences drug efficacy and clinical outcomes. In particular, epigenetics regulates gene expression without changing the DNA sequence. Common types of epigenetic modifications linked to chemoresistance are DNA methylation, histone modification, and non-coding RNAs. This review provides an overview of the current findings of various epigenetic modifications related to cisplatin efficacy in cell lines in vitro and in clinical tumor samples. Furthermore, it discusses whether epigenetic alterations might be used as predictors of the platinum agent response in order to prevent avoidable side effects in patients with resistant malignancies. In addition, epigenetic targeting therapies are described as a possible strategy to render cancer cells more susceptible to platinum drugs.
    Keywords:  cisplatin resistance; epigenetics; histone modification; lncRNA; miRNA; promoter methylation
    DOI:  https://doi.org/10.3390/ijms25021130
  9. Molecules. 2024 Jan 09. pii: 323. [Epub ahead of print]29(2):
    A Two-Step Mechanism for Creating Stable, Condensed Chromatin with the Polycomb Complex PRC1.
    Elias Seif, Nicole J Francis.
      The Drosophila PRC1 complex regulates gene expression by modifying histone proteins and chromatin architecture. Two PRC1 subunits, PSC and Ph, are most implicated in chromatin architecture. In vitro, PRC1 compacts chromatin and inhibits transcription and nucleosome remodeling. The long disordered C-terminal region of PSC (PSC-CTR) is important for these activities, while Ph has little effect. In cells, Ph is important for condensate formation, long-range chromatin interactions, and gene regulation, and its polymerizing sterile alpha motif (SAM) is implicated in these activities. In vitro, truncated Ph containing the SAM and two other conserved domains (mini-Ph) undergoes phase separation with chromatin, suggesting a mechanism for SAM-dependent condensate formation in vivo. How the distinct activities of PSC and Ph on chromatin function together in PRC1 is not known. To address this question, we analyzed structures formed with large chromatin templates and PRC1 in vitro. PRC1 bridges chromatin into extensive fibrillar networks. Ph, its SAM, and SAM polymerization activity have little effect on these structures. Instead, the PSC-CTR controls their growth, and is sufficient for their formation. To understand how phase separation driven by Ph SAM intersects with the chromatin bridging activity of the PSC-CTR, we used mini-Ph to form condensates with chromatin and then challenged them with PRC1 lacking Ph (PRC1ΔPh). PRC1ΔPh converts mini-Ph chromatin condensates into clusters of small non-fusing condensates and bridged fibers. These condensates retain a high level of chromatin compaction and do not intermix. Thus, phase separation of chromatin by mini-Ph, followed by the action of the PSC-CTR, creates a unique chromatin organization with regions of high nucleosome density and extraordinary stability. We discuss how this coordinated sequential activity of two proteins found in the same complex may occur and the possible implications of stable chromatin architectures in maintaining transcription states.
    Keywords:  Polycomb; chromatin; intrinsically disordered region (IDR); phase separation biomolecular condensate; sterile alpha motif (SAM)
    DOI:  https://doi.org/10.3390/molecules29020323
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