bims-ectoca 2024-02-25 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2024‒02‒25
seven papers selected by
Ankita Daiya, BITS Pilani

Diapause-like Drug-Tolerant Persister State: The Key to Nirvana Rebirth.
Association of changes in expression of HDAC and SIRT genes after drug treatment with cancer cell line sensitivity to kinase inhibitors.
Integrative modeling and analysis of signaling crosstalk reveal molecular switches coordinating Yes-associated protein transcriptional activities.
Bivalent chromatin: a developmental balancing act tipped in cancer.
Modified histone peptides uniquely tune the material properties of HP1α condensates.
Immunohistochemical expression of H3.3 G34W in 100 giant cell tumors of bone and its diagnostic mimics, including its value in resolving uncommon diagnostic scenarios: A single institutional study at a tertiary cancer referral center, India.
Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control?

Medicina (Kaunas). 2024 Jan 28. pii: 228. [Epub ahead of print]60(2):

Diapause-like Drug-Tolerant Persister State: The Key to Nirvana Rebirth.

Han-Lin Chen, Wei-Lin Jin.

  Cancer is one of the leading causes of death in the world. Various drugs have been developed to eliminate it but to no avail because a tumor can go into dormancy to avoid therapy. In the past few decades, tumor dormancy has become a popular topic in cancer therapy. Recently, there has been an important breakthrough in the study of tumor dormancy. That is, cancer cells can enter a reversible drug-tolerant persister (DTP) state to avoid therapy, but no exact mechanism has been found. The study of the link between the DTP state and diapause seems to provide an opportunity for a correct understanding of the mechanism of the DTP state. Completely treating cancer and avoiding dormancy by targeting the expression of key genes in diapause are possible. This review delves into the characteristics of the DTP state and its connection with embryonic diapause, and possible treatment strategies are summarized. The authors believe that this review will promote the development of cancer therapy.

Keywords:  cancer relapse; diapause; dormancy; drug resistance; drug-tolerant persister

DOI:  https://doi.org/10.3390/medicina60020228
Epigenetics. 2024 Dec;19(1): 2309824

Association of changes in expression of HDAC and SIRT genes after drug treatment with cancer cell line sensitivity to kinase inhibitors.

Julia Krushkal, Yingdong Zhao, Kyle Roney, Weimin Zhu, Alan Brooks, Deborah Wilsker, Ralph E Parchment, Lisa M McShane, James H Doroshow.

  Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of HDAC and SIRT genes to 15 approved antitumor agents in the NCI-60 cancer cell line panel. Antitumor agents with diverse mechanisms of action induced upregulation or downregulation of multiple HDAC and SIRT genes. HDAC5 was upregulated by dasatinib and erlotinib in the majority of the cell lines. Tumour cell line sensitivity to kinase inhibitors was associated with upregulation of HDAC5, HDAC1, and several SIRT genes. We confirmed changes in HDAC and SIRT expression in independent datasets. We also experimentally validated the upregulation of HDAC5 mRNA and protein expression by dasatinib in the highly sensitive IGROV1 cell line. HDAC5 was not upregulated in the UACC-257 cell line resistant to dasatinib. The effects of cancer drug treatment on expression of HDAC and SIRT genes may influence chemosensitivity and may need to be considered during chemotherapy.

Keywords:  HDAC5; Histone deacetylase; chemosensitivity; dasatinib; sirtuin

DOI:  https://doi.org/10.1080/15592294.2024.2309824
iScience. 2024 Mar 15. 27(3): 109031

Integrative modeling and analysis of signaling crosstalk reveal molecular switches coordinating Yes-associated protein transcriptional activities.

Milad Ghomlaghi, Mandy Theocharous, Nhan Hoang, Sung-Young Shin, Alex von Kriegsheim, Eric O' Neill, Tao Zhang, Lan K Nguyen.

  The transcriptional co-activator YAP forms complexes with distinct transcription factors, controlling cell fate decisions, such as proliferation and apoptosis. However, the mechanisms underlying its context-dependent function are poorly defined. This study explores the interplay between the TGF-β and Hippo pathways and their influence on YAP's association with specific transcription factors. By integrating iterative mathematical modeling with experimental validation, we uncover molecular switches, predominantly controlled by RASSF1A and ITCH, which dictate the formation of YAP-SMAD (proliferative) and YAP-p73 (apoptotic) complexes. Our results show that RASSF1A enhances the formation of apoptotic complexes, whereas ITCH promotes the formation of proliferative complexes. Notably, higher levels of ITCH transform YAP-SMAD activity from a transient to a sustained state, impacting cellular behaviors. Extending these findings to various breast cancer cell lines highlights the role of cellular context in YAP regulation. Our study provides new insights into the mechanisms of YAP transcriptional activities and their therapeutic implications.

Keywords:  Biological sciences; Cell biology

DOI:  https://doi.org/10.1016/j.isci.2024.109031
Biochem Soc Trans. 2024 Feb 22. pii: BST20230426. [Epub ahead of print]

Bivalent chromatin: a developmental balancing act tipped in cancer.

Eleanor Glancy, Natalie Choy, Melanie A Eckersley-Maslin.

  Bivalent chromatin is defined by the co-occurrence of otherwise opposing H3K4me3 and H3K27me3 modifications and is typically located at unmethylated promoters of lowly transcribed genes. In embryonic stem cells, bivalent chromatin has been proposed to poise developmental genes for future activation, silencing or stable repression upon lineage commitment. Normally, bivalent chromatin is kept in tight balance in cells, in part through the activity of the MLL/COMPASS-like and Polycomb repressive complexes that deposit the H3K4me3 and H3K27me3 modifications, respectively, but also emerging novel regulators including DPPA2/4, QSER1, BEND3, TET1 and METTL14. In cancers, both the deregulation of existing domains and the creation of de novo bivalent states is associated with either the activation or silencing of transcriptional programmes. This may facilitate diverse aspects of cancer pathology including epithelial-to-mesenchymal plasticity, chemoresistance and immune evasion. Here, we review current methods for detecting bivalent chromatin and discuss the factors involved in the formation and fine-tuning of bivalent domains. Finally, we examine how the deregulation of chromatin bivalency in the context of cancer could facilitate and/or reflect cancer cell adaptation. We propose a model in which bivalent chromatin represents a dynamic balance between otherwise opposing states, where the underlying DNA sequence is primed for the future activation or repression. Shifting this balance in any direction disrupts the tight equilibrium and tips cells into an altered epigenetic and phenotypic space, facilitating both developmental and cancer processes.

Keywords:  bivalency; bivalent chromatin; epigenetics; gene expression and regulation; histone methylation; methylation

DOI:  https://doi.org/10.1042/BST20230426
bioRxiv. 2024 Feb 09. pii: 2024.02.07.579285. [Epub ahead of print]

Modified histone peptides uniquely tune the material properties of HP1α condensates.

Priyasha Deshpande, Emily Prentice, Alfredo Vidal Ceballos, Patrizia Casaccia, Shana Elbaum-Garfinkle.

Biomolecular condensates have emerged as a powerful new paradigm in cell biology with broad implications to human health and disease, particularly in the nucleus where phase separation is thought to underly elements of chromatin organization and regulation. Specifically, it has been recently reported that phase separation of heterochromatin protein 1alpha (HP1α) with DNA contributes to the formation of condensed chromatin states. HP1α localization to heterochromatic regions is mediated by its binding to specific repressive marks on the tail of histone H3, such as trimethylated lysine 9 on histone H3 (H3K9me3). However, whether epigenetic marks play an active role in modulating the material properties of HP1α and dictating emergent functions of its condensates, remains only partially understood. Here, we leverage a reductionist system, comprised of modified and unmodified histone H3 peptides, HP1α and DNA to examine the contribution of specific epigenetic marks to phase behavior of HP1α. We show that the presence of histone peptides bearing the repressive H3K9me3 is compatible with HP1α condensates, while peptides containing unmodified residues or bearing the transcriptional activation mark H3K4me3 are incompatible with HP1α phase separation. In addition, inspired by the decreased ratio of nuclear H3K9me3 to HP1α detected in cells exposed to uniaxial strain, using fluorescence microscopy and rheological approaches we demonstrate that H3K9me3 histone peptides modulate the dynamics and network properties of HP1α condensates in a concentration dependent manner. These data suggest that HP1α-DNA condensates are viscoelastic materials, whose properties may provide an explanation for the dynamic behavior of heterochromatin in cells in response to mechanostimulation.Statement of significance: The organization of genomic information in eukaryotic cells necessitates compartmentalization into functional domains allowing for the expression of cell identity-specific genes, while repressing genes related to alternative fates. Heterochromatin hosts these transcriptionally silent regions of the genome - which ensure the stability of cell identity -and is characterized by repressive histone marks (H3K9m3) and other specialized proteins (HP1a), recently shown to phase separate with DNA. We show that HP1a forms condensates with DNA which persist in the presence of H3K9me3 peptides. The viscoelastic nature of these condensates depend on H3K9me3:HP1 ratios, which are modulated by mechanical strain in cells. Thus, phase separation may explain the dynamic behavior of heterochromatin in cells, in response to mechanostimulation.

DOI: https://doi.org/10.1101/2024.02.07.579285
Indian J Pathol Microbiol. 2024 Feb 12.

Immunohistochemical expression of H3.3 G34W in 100 giant cell tumors of bone and its diagnostic mimics, including its value in resolving uncommon diagnostic scenarios: A single institutional study at a tertiary cancer referral center, India.

Bharat Rekhi, Vinayak Dave, Ashwin Butle, Bhasker Dharavath, Sonali Khetale, Archana K Redhu, Rudransh Singh, Amit Dutt.

BACKGROUND: There can be a diagnostic challenge in differentiating giant cell tumor of bone (GCTB) from its mimics. Lately, histone H3F3A (Histone 3.3) G34W has been identified as a promising immunohistochemical marker.AIMS: This study was aimed at evaluating H3.3 G34W immunostaining in 100 GCTBs, including its value in resolving diagnostic dilemmas.
MATERIALS AND METHODS: Immunohistochemical staining for H3.3 G34W was graded in terms of staining intensity (1+ to 3+) and the percentage of tumor cells showing crisp nuclear staining.
RESULTS: One hundred GCTBs occurred in 58 males and 42 females (M: F ratio = 1.3), of 7-66 years age (average = 31.3, median = 28), commonly in distal femur (26), followed by proximal tibia (17), distal radius (12), proximal humerus (7), metacarpals (7), sacrum (6), proximal fibula (6), and relatively unusual sites (19), including a single multicentric case. Out of 92 GCTBs, wherein H3.3 G34W immunostaining worked, 81 (88.1%) showed positive staining in the mononuclear cells, including tumors with fibrous histiocytoma-like areas, sparing osteoclast-like giant cells, with 3+ staining intensity in 65/81 (80%) tumors. All 7/7 (100%) malignant GCTBs showed positive staining, including the pleomorphic/sarcomatous cells. All 7/7 (100%) metastatic GCTBs showed positive immunostaining. Seven out of 10 post-denosumab treated GCTBs showed positive H3.3 G34W immunostaining in the residual mononuclear cells. None of the other 37 "giant cell-rich" lesions displayed H3.3 G34W immunostaining. Four of 9 GCTBs tested for H3.3 G34W mutation showed positive results.
CONCLUSIONS: The diagnostic sensitivity and specificity of H3.3 G34W for GCTB were 88.1% and 100%, respectively. This constitutes one of the first reports from our country, further validating the diagnostic value of H3.3 G34W in differentiating GCTB, including metastatic and malignant forms from its mimics, including small biopsy samples. Its value in various diagnostic dilemmas is presented and utility in identifying residual tumor cells in post-denosumab treated GCTBs is worth exploring.

DOI: https://doi.org/10.4103/ijpm.ijpm_886_23
Cell Death Differ. 2024 Feb 20.

Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control?

Ana Janic, Etna Abad, Ivano Amelio.

Genomic instability, a hallmark of cancer, is a direct consequence of the inactivation of the tumor suppressor protein p53. Genetically modified mouse models and human tumor samples have revealed that p53 loss results in extensive chromosomal abnormalities, from copy number alterations to structural rearrangements. In this perspective article we explore the multifaceted relationship between p53, genomic stability, and epigenetic control, highlighting its significance in cancer biology. p53 emerges as a critical regulator of DNA repair mechanisms, influencing key components of repair pathways and directly participating in DNA repair processes. p53 role in genomic integrity however extends beyond its canonical functions. p53 influences also epigenetic landscape, where it modulates DNA methylation and histone modifications. This epigenetic control impacts the expression of genes involved in tumor suppression and oncogenesis. Notably, p53 ability to ensure cellular response to DNA demethylation contributes to the maintenance of genomic stability by preventing unscheduled transcription of repetitive non-coding genomic regions. This latter indicates a causative relationship between the control of epigenetic stability and the maintenance of genomic integrity in p53-mediated tumor suppression. Understanding these mechanisms offers promising avenues for innovative therapeutic strategies targeting epigenetic dysregulation in cancer and emphasizes the need for further research to unravel the complexities of this relationship. Ultimately, these insights hold the potential to transform cancer treatment and prevention strategies.

DOI: https://doi.org/10.1038/s41418-024-01259-9