bims-ectoca 2022-09-18 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022‒09‒18
eight papers selected by
Ankita Daiya
BITS Pilani

TAZ/YAP fusion proteins: mechanistic insights and therapeutic opportunities.
Mitochondrial stress induces AREG expression and epigenomic remodeling through c-JUN and YAP-mediated enhancer activation.
Molecular basis of epigenetic regulation in cancer diagnosis and treatment.
Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters.
LINC-PINT suppresses cisplatin resistance in gastric cancer by inhibiting autophagy activation via epigenetic silencing of ATG5 by EZH2.
Know when to fold 'em: Polycomb complexes in oncogenic 3D genome regulation.
Detection of pan-cancer surface protein biomarkers via a network-based approach on transcriptomics data.
A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.

Trends Cancer. 2022 Sep 09. pii: S2405-8033(22)00173-X. [Epub ahead of print]

TAZ/YAP fusion proteins: mechanistic insights and therapeutic opportunities.

Keith Garcia, Anne-Claude Gingras, Kieran F Harvey, Munir R Tanas.

  The Hippo pathway is dysregulated in many different cancers, but point mutations in the pathway are rare. Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) fusion proteins have emerged in almost all major cancer types and represent the most common genetic mechanism by which the two transcriptional co-activators are activated. Given that the N termini of TAZ or YAP are fused to the C terminus of another transcriptional regulator, the resultant fusion proteins hyperactivate a TEAD transcription factor-based transcriptome. Recent advances show that the C-terminal fusion partners confer oncogenic properties to TAZ/YAP fusion proteins by recruiting epigenetic modifiers that promote a hybrid TEAD-based transcriptome. Elucidating these cooperating epigenetic complexes represents a strategy to identify new therapeutic approaches for a pathway that has been recalcitrant to medical therapy.

Keywords:  TAZ; TEAD transcription factors; YAP; chromatin remodeling; epigenetics; fusion proteins

DOI:  https://doi.org/10.1016/j.trecan.2022.08.002
Nucleic Acids Res. 2022 Sep 12. pii: gkac735. [Epub ahead of print]

Mitochondrial stress induces AREG expression and epigenomic remodeling through c-JUN and YAP-mediated enhancer activation.

Yuko Hino, Katsuya Nagaoka, Shinya Oki, Kan Etoh, Shinjiro Hino, Mitsuyoshi Nakao.

Nucleus-mitochondria crosstalk is essential for cellular and organismal homeostasis. Although anterograde (nucleus-to-mitochondria) pathways have been well characterized, retrograde (mitochondria-to-nucleus) pathways remain to be clarified. Here, we found that mitochondrial dysfunction triggered a retrograde signaling via unique transcriptional and chromatin factors in hepatic cells. Our transcriptomic analysis revealed that the loss of mitochondrial transcription factor A led to mitochondrial dysfunction and dramatically induced expression of amphiregulin (AREG) and other secretory protein genes. AREG expression was also induced by various mitochondria stressors and was upregulated in murine liver injury models, suggesting that AREG expression is a hallmark of mitochondrial damage. Using epigenomic and informatic approaches, we identified that mitochondrial dysfunction-responsive enhancers of AREG gene were activated by c-JUN/YAP1/TEAD axis and were repressed by chromatin remodeler BRG1. Furthermore, while mitochondrial dysfunction-activated enhancers were enriched with JUN and TEAD binding motifs, the repressed enhancers possessed the binding motifs for hepatocyte nuclear factor 4α, suggesting that both stress responsible and cell type-specific enhancers were reprogrammed. Our study revealed that c-JUN and YAP1-mediated enhancer activation shapes the mitochondrial stress-responsive phenotype, which may shift from metabolism to stress adaptation including protein secretion under such stressed conditions.

DOI: https://doi.org/10.1093/nar/gkac735
Front Genet. 2022 ;13 885635

Molecular basis of epigenetic regulation in cancer diagnosis and treatment.

Sonam Tulsyan, Mehreen Aftab, Sandeep Sisodiya, Asiya Khan, Atul Chikara, Pranay Tanwar, Showket Hussain.

  The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally non-invasive biomarkers with clinical applications.

Keywords:  DNA methylation; cancer; cancer therapies; chromatin remodelling; epigenetics; histone modification

DOI:  https://doi.org/10.3389/fgene.2022.885635
iScience. 2022 Sep 16. 25(9): 105013

Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters.

Noortje van Gils, Han J M P Verhagen, Michaël Broux, Tania Martiáñez, Fedor Denkers, Eline Vermue, Arjo Rutten, Tamás Csikós, Sofie Demeyer, Meryem Çil, Marjon Al, Jan Cools, Jeroen J W M Janssen, Gert J Ossenkoppele, Renee X Menezes, Linda Smit.

  Although chemotherapy induces complete remission in the majority of acute myeloid leukemia (AML) patients, many face a relapse. This relapse is caused by survival of chemotherapy-resistant leukemia (stem) cells (measurable residual disease; MRD). Here, we demonstrate that the anthracycline doxorubicin epigenetically reprograms leukemia cells by inducing histone 3 lysine 27 (H3K27) and H3K4 tri-methylation. Within a doxorubicin-sensitive leukemia cell population, we identified a subpopulation of reversible anthracycline-tolerant cells (ATCs) with leukemic stem cell (LSC) features lacking doxorubicin-induced H3K27me3 or H3K4me3 upregulation. These ATCs have a distinct transcriptional landscape than the leukemia bulk and could be eradicated by KDM6 inhibition. In primary AML, reprogramming the transcriptional state by targeting KDM6 reduced MRD load and survival of LSCs residing within MRD, and enhanced chemotherapy response in vivo. Our results reveal plasticity of anthracycline resistance in AML cells and highlight the potential of transcriptional reprogramming by epigenetic-based therapeutics to target chemotherapy-resistant AML cells.

Keywords:  Cancer; Molecular biology; Therapy

DOI:  https://doi.org/10.1016/j.isci.2022.105013
Front Pharmacol. 2022 ;13 968223

LINC-PINT suppresses cisplatin resistance in gastric cancer by inhibiting autophagy activation via epigenetic silencing of ATG5 by EZH2.

Cheng Zhang, Tong Kang, Xinyi Wang, Jizhao Wang, Lin Liu, Jiawei Zhang, Xu Liu, Rong Li, Jiansheng Wang, Jia Zhang.

  Resistance to cisplatin (DDP) is a major obstacle in the clinical treatment of advanced gastric cancer (GC). Long noncoding RNA (lncRNA) play a significant regulatory role in the development and drug resistance of GC. In this study, we reported that the lncRNA LINC-PINT was downregulated in DDP-resistant GC cells. Functional studies showed that LINC-PINT inhibited proliferation and migration of DDP-resistant GC cells in vitro, and overexpression of LINC-PINT could enhance the sensitivity of DDP-resistant GC cells to DDP. Further investigation revealed that LINC-PINT recruited enhancer of zeste homolog 2 (EZH2) to the promotor of ATG5 to inhibit its transcription, leading to the suppression of autophagy and DDP resensitization. Collectively, our results revealed how the LINC-PINT/EZH2/ATG5 axis regulates autophagy and DDP resistance in GC. These data suggest that LINC-PINT may be a potential therapeutic target in GC.

Keywords:  Atg5; DDP-resistance; LINC-PINT; autophagy; gastric cancer

DOI:  https://doi.org/10.3389/fphar.2022.968223
Front Cell Dev Biol. 2022 ;10 986319

Know when to fold 'em: Polycomb complexes in oncogenic 3D genome regulation.

Emma J Doyle, Lluis Morey, Eric Conway.

  Chromatin is spatially and temporally regulated through a series of orchestrated processes resulting in the formation of 3D chromatin structures such as topologically associating domains (TADs), loops and Polycomb Bodies. These structures are closely linked to transcriptional regulation, with loss of control of these processes a frequent feature of cancer and developmental syndromes. One such oncogenic disruption of the 3D genome is through recurrent dysregulation of Polycomb Group Complex (PcG) functions either through genetic mutations, amplification or deletion of genes that encode for PcG proteins. PcG complexes are evolutionarily conserved epigenetic complexes. They are key for early development and are essential transcriptional repressors. PcG complexes include PRC1, PRC2 and PR-DUB which are responsible for the control of the histone modifications H2AK119ub1 and H3K27me3. The spatial distribution of the complexes within the nuclear environment, and their associated modifications have profound effects on the regulation of gene transcription and the 3D genome. Nevertheless, how PcG complexes regulate 3D chromatin organization is still poorly understood. Here we glean insights into the role of PcG complexes in 3D genome regulation and compaction, how these processes go awry during tumorigenesis and the therapeutic implications that result from our insights into these mechanisms.

Keywords:  H2AK119ub1; H3K27me3; Polycomb; cancer; chromatin architecture; compaction; transcription

DOI:  https://doi.org/10.3389/fcell.2022.986319
Brief Bioinform. 2022 Sep 10. pii: bbac400. [Epub ahead of print]

Detection of pan-cancer surface protein biomarkers via a network-based approach on transcriptomics data.

Daniele Mercatelli, Chiara Cabrelle, Pierangelo Veltri, Federico M Giorgi, Pietro H Guzzi.

  Cell surface proteins have been used as diagnostic and prognostic markers in cancer research and as targets for the development of anticancer agents. Many of these proteins lie at the top of signaling cascades regulating cell responses and gene expression, therefore acting as 'signaling hubs'. It has been previously demonstrated that the integrated network analysis on transcriptomic data is able to infer cell surface protein activity in breast cancer. Such an approach has been implemented in a publicly available method called 'SURFACER'. SURFACER implements a network-based analysis of transcriptomic data focusing on the overall activity of curated surface proteins, with the final aim to identify those proteins driving major phenotypic changes at a network level, named surface signaling hubs. Here, we show the ability of SURFACER to discover relevant knowledge within and across cancer datasets. We also show how different cancers can be stratified in surface-activity-specific groups. Our strategy may identify cancer-wide markers to design targeted therapies and biomarker-based diagnostic approaches.

Keywords:  bioinformatics; biological networks; biomarkers; surfaceome; transcriptomics

DOI:  https://doi.org/10.1093/bib/bbac400
Front Oncol. 2022 ;12 962928

A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.

Eric A Hanse, Mei Kong.

  A paradox of fast-proliferating tumor cells is that they deplete extracellular nutrients that often results in a nutrient poor microenvironment in vivo. Having a better understanding of the adaptation mechanisms cells exhibit in response to metabolic stress will open new therapeutic windows targeting the tumor's extreme nutrient microenvironment. Glutamine is one of the most depleted amino acids in the tumor core and here, we provide insight into how important glutamine and its downstream by-product, α-ketoglutarate (αKG), are to communicating information about the nutrient environment. This communication is key in the cell's ability to foster adaptation. We highlight the epigenetic changes brought on when αKG concentrations are altered in cancer and discuss how depriving cells of glutamine may lead to cancer cell de-differentiation and the ability to grow and thrive in foreign environments. When we starve cells, they adapt to survive. Those survival "skills" allow them to go out looking for other places to live and metastasize. We further examine current challenges to modelling the metabolic tumor microenvironment in the laboratory and discuss strategies that consider current findings to target the tumor's poor nutrient microenvironment.

Keywords:  alpha ketoglutarate; epigenetics; glutamine; glutaminolysis-inhibition; metabolism; tumor; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.962928