bims-ectoca 2023-03-05 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023–03–05
nine papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Epigenetic Regulations in Mammalian Cells: Roles and Profiling Techniques.
EZH2 W113C is a gain-of-function mutation in B cell lymphoma enabling both PRC2 methyltransferase activation and tazemetostat resistance.
Oncogenic YAP mediates changes in chromatin accessibility and activity that drive cell cycle gene expression and cell migration.
DEPDC1 and KIF4A synergistically inhibit the malignant biological behavior of osteosarcoma cells through Hippo signaling pathway.
Recent progress and challenges in single-cell imaging of enhancer-promoter interaction.
Bleb protrusions help cancer cells to cheat death.
Transfer of exosomal microRNAs confers doxorubicin resistance in osteosarcoma cells.
Extended preconditioning on soft matrices directs human mesenchymal stem cell fate via YAP transcriptional activity and chromatin organization.
Neighborhood deprivation, racial segregation and associations with cancer risk and outcomes across the cancer-control continuum.

Mol Cells. 2023 Feb 28. 46(2): 86-98

Epigenetic Regulations in Mammalian Cells: Roles and Profiling Techniques.

Uijin Kim, Dong-Sung Lee.

  The genome is almost identical in all the cells of the body. However, the functions and morphologies of each cell are different, and the factors that determine them are the genes and proteins expressed in the cells. Over the past decades, studies on epigenetic information, such as DNA methylation, histone modifications, chromatin accessibility, and chromatin conformation have shown that these properties play a fundamental role in gene regulation. Furthermore, various diseases such as cancer have been found to be associated with epigenetic mechanisms. In this study, we summarized the biological properties of epigenetics and single-cell epigenomic profiling techniques, and discussed future challenges in the field of epigenetics.

Keywords:  3D chromatin structure; DNA methylation; RNA modification; histone modification; single-cell epigenomics

DOI:  https://doi.org/10.14348/molcells.2023.0013
J Biol Chem. 2023 Feb 27. pii: S0021-9258(23)00205-3. [Epub ahead of print] 103073

EZH2 W113C is a gain-of-function mutation in B cell lymphoma enabling both PRC2 methyltransferase activation and tazemetostat resistance.

Liping Chu, Dongxia Tan, Meimei Zhu, Yuxiu Qu, Xin Ma, Bao-Liang Song, Wei Qi.

  Polycomb Repressive Complex2 (PRC2) suppresses gene transcription by methylating lysine 27 of histone H3 (H3K27) and plays critical roles in embryonic development. Among the core PRC2 subunits, EZH2 is the catalytic subunit and EED allosterically activates EZH2 upon binding trimethylated H3K27 (H3K27me3). Activating mutations on Y641, A677, and A687 within the enzymatic SET domain of EZH2 have been associated with enhanced H3K27me3 and tumorigenicity of many cancers including B-cell lymphoma and melanoma. To tackle the critical residues outside the EZH2 SET domain, we examined EZH2 mutations in lymphoma from cancer genome databases and identified a novel gain-of-function (GoF) mutation W113C, which increases H3K27me3 in vitro and in vivo and promotes CDKN2A silencing to a similar level as the EZH2 Y641F. Different from other GoF mutations, this mutation is located in the SAL motif at the EZH2 N-terminus, which stabilizes the SET domain and facilitates substrate binding. This may explain how the W113C mutation increases PRC2 activity. Tazemetostat is an FDA-approved EZH2 binding inhibitor for follicular lymphoma treatment. Intriguingly, the W113C mutation leads to tazemetostat-resistance in cell and in vivo in both H3K27 methylation and tumor proliferation. Another class of allosteric PRC2 inhibitor binding EED overcomes the resistance, effectively decreases H3K27me3, and blocks tumor proliferation in cells expressing EZH2 W113C. As this mutation is originally identified from lymphoma samples, our results demonstrated its activating characteristic and the deleterious consequence, provide insights on PRC2 regulation, and support the continued exploration of treatment optimization for lymphoma patients.

Keywords:  EZH2; PRC2 inhibitor; drug resistance; epigenetics; histone methylation; lymphoma; methyltransferase

DOI:  https://doi.org/10.1016/j.jbc.2023.103073
Nucleic Acids Res. 2023 Mar 02. pii: gkad107. [Epub ahead of print]

Oncogenic YAP mediates changes in chromatin accessibility and activity that drive cell cycle gene expression and cell migration.

Maria Camila Fetiva, Franziska Liss, Dörthe Gertzmann, Julius Thomas, Benedikt Gantert, Magdalena Vogl, Nataliia Sira, Grit Weinstock, Susanne Kneitz, Carsten P Ade, Stefan Gaubatz.

YAP, the key protein effector of the Hippo pathway, is a transcriptional co-activator that controls the expression of cell cycle genes, promotes cell growth and proliferation and regulates organ size. YAP modulates gene transcription by binding to distal enhancers, but the mechanisms of gene regulation by YAP-bound enhancers remain poorly understood. Here we show that constitutive active YAP5SA leads to widespread changes in chromatin accessibility in untransformed MCF10A cells. Newly accessible regions include YAP-bound enhancers that mediate activation of cycle genes regulated by the Myb-MuvB (MMB) complex. By CRISPR-interference we identify a role for YAP-bound enhancers in phosphorylation of Pol II at Ser5 at MMB-regulated promoters, extending previously published studies that suggested YAP primarily regulates the pause-release step and transcriptional elongation. YAP5SA also leads to less accessible 'closed' chromatin regions, which are not directly YAP-bound but which contain binding motifs for the p53 family of transcription factors. Diminished accessibility at these regions is, at least in part, a consequence of reduced expression and chromatin-binding of the p53 family member ΔNp63 resulting in downregulation of ΔNp63-target genes and promoting YAP-mediated cell migration. In summary, our studies uncover changes in chromatin accessibility and activity that contribute to the oncogenic activities of YAP.

DOI: https://doi.org/10.1093/nar/gkad107
J Orthop Surg Res. 2023 Feb 27. 18(1): 145

DEPDC1 and KIF4A synergistically inhibit the malignant biological behavior of osteosarcoma cells through Hippo signaling pathway.

Mingming Yang, Hang Zhang, Shichang Gao, Wei Huang.

  The treatment of osteosarcoma (OS) is still mainly surgery combined with systematic chemotherapy, and gene therapy is expected to improve the survival rate of patients. This study aimed to explore the effect of DEP domain 1 protein (DEPDC1) and kinesin super-family protein 4A (KIF4A) in OS and understand its mechanism. Th expression of DEPDC1 and KIF4A in OS cells was detected by RT-PCR and western blot. The viability, proliferation, invasion and migration of OS cells and tube formation of human umbilical vein endothelial cells (HUVECs) after indicated treatment were in turn detected by CCK-8 assay, EdU staining, wound healing assay, transwell assay and tube formation assay. The interaction between DEPDC1 and KIF4A was predicted by STRING and confirmed by co-immunoprecipitation. The expression of epithelial-mesenchymal transition (EMT)-related proteins, tube formation-related proteins and Hippo signaling pathway proteins was detected by western blot. As a result, the expression of DEPDC1 and KIF4A was all increased in U2OS cells. Down-regulation of DEPDC1 suppressed the viability, proliferation, invasion and migration of U2OS cells and tube formation of HUVECs, accompanied by the increased expression of E-cadherin and decreased expression of N-cadherin, Vimentin and VEGF. DEPDC1 was confirmed to be interacted with KIF4A. Upregulation of KIF4A partially reversed the effect of DEPDC1 interference on the above biological behaviors of U2OS cells. Down-regulation of DEPDC1 promoted the expression of p-LATS1 and p-YAP in Hippo signaling pathway, which was reversed by upregulation of KIF4A. In conclusion, down-regulation of DEPDC1 inhibited the malignant biological behavior of OS cells through the activation of Hippo signaling pathway, which could be reversed by upregulation of KIF4A.

Keywords:  DEPDC1; Hippo signaling pathway; KIF4A; Osteosarcoma cells

DOI:  https://doi.org/10.1186/s13018-023-03572-4
Curr Opin Genet Dev. 2023 Feb 26. pii: S0959-437X(23)00003-5. [Epub ahead of print]79 102023

Recent progress and challenges in single-cell imaging of enhancer-promoter interaction.

Liang-Fu Chen, Joo Lee, Alistair Boettiger.

In the past two years, approaches relying on high-resolution microscopy and live-cell imaging have increasingly contributed to our understanding of the 3D genome organization and its importance for transcriptional control. Here, we describe recent progress that has highlighted how flexible and heterogeneous 3D chromatin structure is, on the length scales relevant to transcriptional control. We describe work that has investigated how robust transcriptional outcomes may be derived from such flexible organization without the need for clearly distinct structures in active and silent cells. We survey the latest state of the art in directly observing the dynamics of chromatin interactions, and suggest how some recent, apparently contradictory conclusions may be reconciled.

DOI: https://doi.org/10.1016/j.gde.2023.102023
Nature. 2023 Mar 01.

Bleb protrusions help cancer cells to cheat death.

Michal Reichman-Fried, Erez Raz.



Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-023-00477-4
Mol Med Rep. 2023 Apr;pii: 86. [Epub ahead of print]27(4):

Transfer of exosomal microRNAs confers doxorubicin resistance in osteosarcoma cells.

Tao Cai, Chunlin Zhang, Taichen Zhan.

  Osteosarcoma (OS) is the commonest primary malignant bone tumor in children and adolescents. However, chemotherapy resistance is a major challenge for the treatment of OS. Exosomes have been reported to serve an increasingly important role in different stages of tumor progression and chemotherapy resistance. The present study investigated whether exosomes derived from doxorubicin‑resistant OS cells (MG63/DXR) could be taken up in doxorubicin‑sensitive OS cells (MG63) and induce a doxorubicin‑resistant phenotype. MDR‑1, as the specific mRNA of chemoresistance, can be transferred by exosomes from MG63/DXR cells to MG63 cells. In addition, the present study identified 2,864 differentially expressed miRNAs (456 upregulated and 98 downregulated with fold‑change >2.0, P<5x10‑2, and FDR<0.05) in all three sets of exosomes from MG63/DXR cells and MG63 cells. The related miRNAs and pathways of exosomes involved in the doxorubicin resistance were identified by bioinformatic analysis. A total of 10 randomly selected exosomal miRNAs were dysregulated in exosomes from MG63/DXR cells relative to MG63 cells by reverse transcription‑quantitative PCR detection. As a result, miR‑143‑3p was found high expressed in exosomes from doxorubicin‑resistant OS cells compared with doxorubicin‑sensitive OS cells and upregulation of exosomal miR‑143‑3p abundance associated with the poor chemotherapeutic response to OS cells. Briefly, transfer of exosomal miR‑143‑3p confers doxorubicin resistance in osteosarcoma cells.

Keywords:  chemoresistance; exosome; microRNA; osteosarcoma

DOI:  https://doi.org/10.3892/mmr.2023.12973
APL Bioeng. 2023 Mar;7(1): 016110

Extended preconditioning on soft matrices directs human mesenchymal stem cell fate via YAP transcriptional activity and chromatin organization.

Yufei Ma, Xu Zhang, Shaoxin Tang, Li Xue, Jing Wang, Xiaohui Zhang.

Dynamic extracellular matrix (ECM) mechanics plays a crucial role in tissue development and disease progression through regulation of stem cell behavior, differentiation, and fate determination. Periodontitis is a typical case characterized by decreased ECM stiffness within diseased periodontal tissues as well as with irreversible loss of osteogenesis capacity of periodontal tissue-derived human periodontal tissue-derived MSCs (hMSCs) even returning back to a physiological mechanical microenvironment. We hypothesized that the hMSCs extendedly residing in the soft ECM of diseased periodontal tissues may memorize the mechanical information and have further effect on ultimate cell fate besides the current mechanical microenvironment. Using a soft priming and subsequent stiff culture system based on collagen-modified polydimethylsiloxane substrates, we were able to discover that extended preconditioning on soft matrices (e.g., 7 days of exposure) led to approximately one-third decrease in cell spreading, two-third decrease in osteogenic markers (e.g., RUNX2 and OPN) of hMSCs, and one-thirteenth decrease in the production of mineralized nodules. The significant loss of osteogenic ability may attribute to the long-term residing of hMSCs in diseased periodontal tissue featured with reduced stiffness. This is associated with the regulation of transcriptional activity through alterations of subcellular localization of yes-associated protein and nuclear feature-mediated chromatin organization. Collectively, we reconstructed phenomena of irreversible loss of hMSC osteogenesis capacity in diseased periodontal tissues in our system and revealed the critical effect of preconditioning duration on soft matrices as well as the potential mechanisms in determining ultimate hMSC fate.

DOI: https://doi.org/10.1063/5.0124424
Mol Psychiatry. 2023 Mar 03.

Neighborhood deprivation, racial segregation and associations with cancer risk and outcomes across the cancer-control continuum.

Bernard F Fuemmeler, Jie Shen, Hua Zhao, Robert Winn.

The racial/ethnic disparities in cancer incidence and outcome are partially due to the inequities in neighborhood advantage. Mounting evidences supported a link between neighborhood deprivation and cancer outcomes including higher mortality. In this review, we discuss some of the findings related to work on area-level neighborhood variables and cancer outcomes, and the potential biological and built/natural environmental mechanisms that might explain this link. Studies have also shown that residents of deprived neighborhoods or of racially or economically segregated neighborhoods have worse health outcomes than residents of more affluent neighborhoods and/or less racially or economically segregated neighborhoods, even after adjusting for the individual-level socioeconomic status. To date, little research has been conducted investigating the biological mediators that may play roles in the associations of neighborhood deprivation and segregation with cancer outcomes. The psychophysiological stress induced by neighborhood disadvantage among people living in these neighborhoods could be a potential underlying biological mechanism. We examined a number of chronic stress-related pathways that may potentially mediate the relationship between area-level neighborhood factors and cancer outcomes, including higher allostatic load, stress hormones, altered epigenome and telomere maintenance and biological aging. In conclusion, the extant evidence supports the notion that neighborhood deprivation and racial segregation have unfavorable impacts on cancer. Understanding how neighborhood factors influence the biological stress response has the potential to inform where and what types of resources are needed within the community to improve cancer outcomes and reduce disparities. More studies are warranted to directly assess the role of biological and social mechanisms in mediating the relationship between neighborhood factors and cancer outcomes.

DOI: https://doi.org/10.1038/s41380-023-02006-1