bims-ectoca 2022-08-07 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022–08–07
eight papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Emerging Themes in Mechanisms of Tumorigenesis by SWI/SNF Subunit Mutation.
The Hippo-YAP/TAZ Signaling Pathway in Intestinal Self-Renewal and Regeneration After Injury.
Single-Cell RNA Sequencing: Unravelling the Bone One Cell at a Time.
Therapeutic potential of inhibiting histone 3 lysine 27 demethylases: a review of the literature.
Nuclear β-catenin translocation plays a key role in osteoblast differentiation of giant cell tumor of bone.
Relationship between Yes-Associated Protein 1 and Prognosis of Digestive System Neoplasm: Quantitative Analysis and Bioinformatics Analysis Based on 4023 Patients.
Targeting the Hippo/YAP/TAZ signaling pathway: novel opportunities for therapeutic interventions into skin cancers.
Overall Survival, Progression-Free Survival, and Tumor Response Benefit Supporting Initial US Food and Drug Administration Approval and Indication Extension of New Cancer Drugs, 2003-2021.

Epigenet Insights. 2022 ;15 25168657221115656

Emerging Themes in Mechanisms of Tumorigenesis by SWI/SNF Subunit Mutation.

Cheyenne A Jones, William P Tansey, April M Weissmiller.

  The SWI/SNF chromatin remodeling complex uses the energy of ATP hydrolysis to alter contacts between DNA and nucleosomes, allowing regions of the genome to become accessible for biological processes such as transcription. The SWI/SNF chromatin remodeler is also one of the most frequently altered protein complexes in cancer, with upwards of 20% of all cancers carrying mutations in a SWI/SNF subunit. Intense studies over the last decade have probed the molecular events associated with SWI/SNF dysfunction in cancer and common themes are beginning to emerge in how tumor-associated SWI/SNF mutations promote malignancy. In this review, we summarize current understanding of SWI/SNF complexes, their alterations in cancer, and what is known about the impact of these mutations on tumor-relevant transcriptional events. We discuss how enhancer dysregulation is a common theme in SWI/SNF mutant cancers and describe how resultant alterations in enhancer and super-enhancer activity conspire to block development and differentiation while promoting stemness and self-renewal. We also identify a second emerging theme in which SWI/SNF perturbations intersect with potent oncoprotein transcription factors AP-1 and MYC to drive malignant transcriptional programs.

Keywords:  AP-1; ARID1A; BRG1; MYC; SNF5; SWI/SNF; chromatin accessibility; chromatin remodeling; enhancers; oncogene; tumor suppressor

DOI:  https://doi.org/10.1177/25168657221115656
Front Cell Dev Biol. 2022 ;10 894737

The Hippo-YAP/TAZ Signaling Pathway in Intestinal Self-Renewal and Regeneration After Injury.

Feihong Deng, Zengrong Wu, Fei Zou, Su Wang, Xuehong Wang.

  The Hippo pathway and its downstream effectors, the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), control stem cell fate and cell proliferation and differentiation and are essential for tissue self-renewal and regeneration. YAP/TAZ are the core components of the Hippo pathway and they coregulate transcription when localized in the nucleus. The intestinal epithelium undergoes well-regulated self-renewal and regeneration programs to maintain the structural and functional integrity of the epithelial barrier. This prevents luminal pathogen attack, and facilitates daily nutrient absorption and immune balance. Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the entire digestive tract. Impaired mucosal healing is a prominent biological feature of IBD. Intestinal self-renewal is primarily dependent on functional intestinal stem cells (ISCs), especially Lgr5+ crypt base columnar (CBC) cells and transient-amplifying (TA) cells in the crypt base. However, intestinal wound healing is a complicated process that is often associated with epithelial cells, and mesenchymal and immune cells in the mucosal microenvironment. Upon intestinal injury, nonproliferative cells rapidly migrate towards the wound bed to reseal the damaged epithelium, which is followed by cell proliferation and differentiation. YAP is generally localized in the nucleus of Lgr5+ CBC cells, where it transcriptionally regulates the expression of the ISC marker Lgr5 and plays an important role in intestinal self-renewal. YAP/TAZ are the primary mechanical sensors of the cellular microenvironment. Their functions include expanding progenitor and stem cell populations, reprogramming differentiated cells into a primitive state, and mediating the regenerative function of reserve stem cells. Thus, YAP/TAZ play extremely crucial roles in epithelial repair after damage. This review provides an overview of the Hippo-YAP/TAZ signaling pathway and the processes of intestinal self-renewal and regeneration. In particular, we summarize the roles of YAP/TAZ in the phases of intestinal self-renewal and regeneration to suggest a potential strategy for IBD treatment.

Keywords:  hippo–YAP/TAZ pathway; inflammatory bowel disease; intestinal regeneration; intestinal self-renewal; intestinal stem cell

DOI:  https://doi.org/10.3389/fcell.2022.894737
Curr Osteoporos Rep. 2022 Aug 02.

Single-Cell RNA Sequencing: Unravelling the Bone One Cell at a Time.

Ryan C Chai.

   PURPOSE OF REVIEW: Bone is a complex tissue populated by a highly heterogeneous mix of cell types in different compartments. The endosteal compartment is a key site for bone remodelling and provides a supportive microenvironment to harbour haematopoietic and mesenchymal stem cells, as well as cancer cells that grow in bone. The purpose of this review is to summarize recent findings of studies in bone using single-cell RNA sequencing and emergent spatial RNA sequencing to describe different bone-resident cell types and their molecular programs.
RECENT FINDINGS: Single-cell RNA sequencing identified novel and transcriptionally distinct cell clusters within different bone cell lineages, including MSCs, osteoblasts, chondrocytes, fibroblasts, osteoclasts and cells of the vasculature. Spatial transcriptomics methods provide information on the localization of the different cell populations. Single-cell transcriptomics provided valuable insights into long-standing knowledge gaps in the cellular heterogeneity of bone-resident cells in unprecedented detail, paving the way for studies to further investigate the different cell populations and to develop cell-based therapies for bone diseases.

Keywords:  Bone; Mesenchymal stromal cells (MSCs); Microenvironment; Osteoblasts; Osteoclasts; Single-cell RNA-seq (scRNAseq)

DOI:  https://doi.org/10.1007/s11914-022-00735-w
Clin Epigenetics. 2022 Aug 01. 14(1): 98

Therapeutic potential of inhibiting histone 3 lysine 27 demethylases: a review of the literature.

Jeries Abu-Hanna, Jigisha A Patel, Evangelos Anastasakis, Richard Cohen, Lucie H Clapp, Marilena Loizidou, Mohammad M R Eddama.

  Histone 3 lysine 27 (H3K27) demethylation constitutes an important epigenetic mechanism of gene activation. It is mediated by the Jumonji C domain-containing lysine demethylases KDM6A and KDM6B, both of which have been implicated in a wide myriad of diseases, including blood and solid tumours, autoimmune and inflammatory disorders, and infectious diseases. Here, we review and summarise the pre-clinical evidence, both in vitro and in vivo, in support of the therapeutic potential of inhibiting H3K27-targeting demethylases, with a focus on the small-molecule inhibitor GSK-J4. In malignancies, KDM6A/B inhibition possesses the ability to inhibit proliferation, induce apoptosis, promote differentiation, and heighten sensitivity to currently employed chemotherapeutics. KDM6A/B inhibition also comprises a potent anti-inflammatory approach in inflammatory and autoimmune disorders associated with inappropriately exuberant inflammatory and autoimmune responses, restoring immunological homeostasis to inflamed tissues. With respect to infectious diseases, KDM6A/B inhibition can suppress the growth of infectious pathogens and attenuate the immunopathology precipitated by these pathogens. The pre-clinical in vitro and in vivo data, summarised in this review, suggest that inhibiting H3K27 demethylases holds immense therapeutic potential in many diseases.

Keywords:  Autoimmune diseases; Cancer; Epigenetics; GSK-J4; H3K27; Histone lysine demethylase; Infectious diseases; Inflammation; JMJD3; KDM6A; KDM6B; UTX

DOI:  https://doi.org/10.1186/s13148-022-01305-8
Sci Rep. 2022 Aug 04. 12(1): 13438

Nuclear β-catenin translocation plays a key role in osteoblast differentiation of giant cell tumor of bone.

Atsushi Kimura, Yu Toda, Yoshihiro Matsumoto, Hidetaka Yamamoto, Kenichiro Yahiro, Eijiro Shimada, Masaya Kanahori, Ryunosuke Oyama, Suguru Fukushima, Makoto Nakagawa, Nokitaka Setsu, Makoto Endo, Toshifumi Fujiwara, Tomoya Matsunobu, Yoshinao Oda, Yasuharu Nakashima.

Denosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker regarding tumor ossification of GCTB has not been elucidated. In this study, we investigated the relationship between Wnt/β-catenin signaling and the ossification of GCTB and evaluated whether endogenous nuclear β-catenin expression predicted denosumab-induced bone formation in GCTB. Genuine patient-derived primary GCTB tumor stromal cells exhibited osteoblastic characteristics. Identified osteoblastic markers and nuclear β-catenin translocation were significantly upregulated via differentiation induction and were inhibited by treating with Wnt signaling inhibitor, GGTI-286, or selective Rac1-LEF inhibitor, NSC23766. Furthermore, we reviewed the endogenous ossification and nuclear β-catenin translocation of 86 GCTB clinical samples and elucidated that intra-tumoral ossification was significantly associated with the nuclear translocation. Three-dimensional quantitative analyses (n = 13) of tumoral CT images have revealed that the nuclear β-catenin translocation of naïve GCTB samples was significantly involved with the denosumab-induced tumor ossification. Our findings suggest a close relationship between the nuclear β-catenin translocation and the osteoblastic differentiation of GCTB. Investigations of the nuclear β-catenin in naïve GCTB samples may provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.

DOI: https://doi.org/10.1038/s41598-022-17728-5
Evid Based Complement Alternat Med. 2022 ;2022 3798694

Relationship between Yes-Associated Protein 1 and Prognosis of Digestive System Neoplasm: Quantitative Analysis and Bioinformatics Analysis Based on 4023 Patients.

Luo Yuan Yuan, Wu Shuai, Zou Yuan-Peng, Jiang Ting, Xia Wei, He Yu-Qin.

Yes-associated protein 1 (YAP1) is involved in the development of a variety of malignancies. However, the prognosis of malignant digestive tumors with YAP1 expression is still controversial. This study searched 31 articles with 36 data sets of 4023 patients to explore the role of YAP1 expression on the prognosis of digestive malignant tumors by searching the PubMed, Embase, Web of Science, Google Scholar, and Cochrane Library databases. Specifically, relevant cancer expression matrix data were downloaded from The Cancer Genome Atlas (TCGA) database. In this meta-analysis, quantitative analysis showed that the overexpression of YAP1 was not conducive to OS (1.62, 95% CI (1.38, 1.90), P=0.001) and DFS (1.59, 95% CI (1.31, 1.93), P=0.001) in patients with digestive malignant tumors. In addition, TCGA database analysis showed that YAP1 was overexpressed in gastric cancer, cholangiocarcinoma, and colorectal cancer. Survival analysis showed that the patients with high expression of YAP1 in pancreatic cancer have a poor OS (MST: 394 vs. 691 days, P < 0.0001) and DFS (MST: 371 vs. 542 days, P=0.026) prognosis. YAP1 may be a molecular marker that effectively predicts the survival of malignant digestive tumors, especially pancreatic cancer, and is a potential therapeutic target for malignant digestive tumors.

DOI: https://doi.org/10.1155/2022/3798694
Exp Dermatol. 2022 Aug 01.

Targeting the Hippo/YAP/TAZ signaling pathway: novel opportunities for therapeutic interventions into skin cancers.

Alexander Howard, Jodie Bojko, Benjamin Flynn, Sophie Bowen, Ute Jungwirth, Gernot Walko.

  Skin cancers are by far the most frequently diagnosed human cancers. The closely related transcriptional co-regulator proteins YAP and TAZ (WWTR1) have emerged as important drivers of tumor initiation, progression and metastasis in melanoma and non-melanoma skin cancers. YAP/TAZ serve as an essential signaling hub by integrating signals from multiple upstream pathways. In this review, we summarize the roles of YAP/TAZ in skin physiology and tumorigenesis and discuss recent efforts of therapeutic interventions that target YAP/TAZ in in both preclinical and clinical settings, as well as their prospects for use as skin cancer treatments.

Keywords:  Epidermis; Hippo signaling; basal cell carcinoma; melanoma; skin cancer; squamous cell carcinoma

DOI:  https://doi.org/10.1111/exd.14655
J Clin Oncol. 2022 Aug 03. JCO2200535

Overall Survival, Progression-Free Survival, and Tumor Response Benefit Supporting Initial US Food and Drug Administration Approval and Indication Extension of New Cancer Drugs, 2003-2021.

Daniel Tobias Michaeli, Thomas Michaeli.

PURPOSE: Clinical trial evidence is routinely evaluated for initial drug approvals, yet the benefit of indication extensions remains uncertain. This study evaluates the clinical benefit supporting new cancer drugs' initial and supplemental US Food and Drug Administration (FDA) indication approval.
PATIENTS AND METHODS: Clinical trial evidence supporting each indication's FDA approval was collected from the Drugs@FDA database between 2003 and 2021. Drug, indication, and clinical trial characteristics are described. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk for tumor response were meta-analyzed.
RESULTS: Out of 124 FDA-approved drugs, 78 were approved across multiple indications. Out of 374 indications, 141 were approved as combination therapies, 255 for solid cancers, 121 with biomarkers, and 182 as first-line therapy. Approval was mostly supported by open-label (267 [71%]) phase III (238 [64%]) concurrent randomized controlled trials (248 [66%]) with a median of 331 enrolled patients (interquartile range [IQR], 123-665 patients). Across 234 randomized controlled trials with available data, drugs' HRs were 0.73 (95% CI, 0.72 to 0.75; I2 = 29.6%) for OS and 0.57 (95% CI, 0.54 to 0.60; I2 = 90.6%) for PFS, whereas tumor response was 1.38 (95% CI, 1.33 to 1.42; I2 = 80.7%). Novel pharmaceuticals increased patient survival by a median of 2.80 months (IQR, 1.97-4.60 months) for OS and 3.30 months (IQR, 1.50-5.58 months) for PFS. Initial indications more frequently received accelerated approval, supported by single-arm trials for advanced-line monotherapies, than indication extensions. Initial approvals provided a higher PFS (HR, 0.48 v 0.58; P = .002) and tumor response (relative risk, 1.76 v 1.36; P < .001).
CONCLUSION: New cancer drugs substantially reduce the risk of death and tumor progression, yet only marginally extend patient survival. The FDA, physicians, patients, and insurers must evaluate and decide on a drug's safety and efficacy approval, pricing, coverage, and reimbursement on an indication-specific level.

DOI: https://doi.org/10.1200/JCO.22.00535