bims-ectoca 2024-06-09 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2024–06–09
six papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Intrinsic epigenetic state of primary osteosarcoma drives metastasis.
Protective Role of Nanoceria-Infused Nanofibrous Scaffold toward Bone Tissue Regeneration with Senescent Cells.
Chemosensitizing effect of pentoxifylline in sensitive and multidrug-resistant non-small cell lung cancer cells.
Hdac3-deficiency increases senescence-associated distention of satellite DNA and telomere-associated foci in osteoprogenitor cells.
Di- and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair.
The PRC2 complex epigenetically silences GATA4 to suppress cellular senescence and promote the progression of breast cancer.

Mol Cancer Res. 2024 Jun 06.

Intrinsic epigenetic state of primary osteosarcoma drives metastasis.

Irtisha Singh, Nino Rainusso, Lyazat Kurenbekova, Bikesh K Nirala, Juan Dou, Abhinaya Muruganandham, Jason T Yustein.

Osteosarcoma (OS) is the most common primary malignant bone tumor affecting the pediatric population with high potential to metastasize. However, insights into the molecular features enabling its metastatic potential are limited. We mapped the active chromatin landscapes of OS tumors by integrating histone H3 lysine acetylated chromatin state (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary OS tumors from patients with metastasis (primary met) have a distinct active chromatin landscape compared to those without metastasis (localized). This difference shapes the transcriptional profile of OS. We identified novel candidate genes, including PPP1R1B, PREX1 and IGF2BP1, which exhibit increased chromatin activity in primary met. Loss of PREX1 in primary met OS cells significantly diminishes OS proliferation, invasion, migration, and colony formation capacity. Differential chromatin activity in primary met is associated with genes regulating cytoskeleton organization, cellular adhesion, and extracellular matrix suggestive of their role in facilitating OS metastasis. Chromatin profiling of tumors from metastatic lung lesions shows increased chromatin activity in genes involved in cell migration and Wnt pathway. This data demonstrates that metastatic potential is intrinsically present in primary metastatic tumors, with cellular chromatin profiles further adapting for successful dissemination, migration, and colonization at the distal site. Implications: Our study demonstrates that metastatic potential is intrinsic to primary metastatic osteosarcoma tumors, with chromatin profiles further adapting for successful dissemination, migration and colonization at distal metastatic site.

DOI: https://doi.org/10.1158/1541-7786.MCR-23-0055
Biomacromolecules. 2024 Jun 05.

Protective Role of Nanoceria-Infused Nanofibrous Scaffold toward Bone Tissue Regeneration with Senescent Cells.

Sagar Nilawar, Parul Yadav, Nipun Jain, Deepak Kumar Saini, Kaushik Chatterjee.

The presence of oxidative stress in bone defects leads to delayed regeneration, especially in the aged population and patients receiving cancer treatment. This delay is attributed to the increased levels of reactive oxygen species (ROS) in these populations due to the accumulation of senescent cells. Tissue-engineered scaffolds are emerging as an alternative method to treat bone defects. In this study, we engineered tissue scaffolds tailored to modulate the adverse effects of oxidative stress and promote bone regeneration. We used polycaprolactone to fabricate nanofibrous mats by using electrospinning. We exploited the ROS-scavenging properties of cerium oxide nanoparticles to alleviate the high oxidative stress microenvironment caused by the presence of senescent cells. We characterized the nanofibers for their physical and mechanical properties and utilized an ionization-radiation-based model to induce senescence in bone cells. We demonstrate that the presence of ceria can modulate ROS levels, thereby reducing the level of senescence and promoting osteogenesis. Overall, this study demonstrates that ceria-infused nanofibrous scaffolds can be used for augmenting the osteogenic activity of senescent progenitor cells, which has important implications for engineering bone tissue scaffolds for patients with low regeneration capabilities.

DOI: https://doi.org/10.1021/acs.biomac.4c00184
Cancer Drug Resist. 2024 ;7 19

Chemosensitizing effect of pentoxifylline in sensitive and multidrug-resistant non-small cell lung cancer cells.

Beatriz S Matos, Sara Peixoto da Silva, M Helena Vasconcelos, Cristina P R Xavier.

  Aim: Multidrug resistance (MDR) is frequent in non-small cell lung cancer (NSCLC) patients, which can be due to its fibrotic stroma. This work explores the combination of pentoxifylline, an anti-fibrotic and chitinase 3-like-1 (CHI3L1) inhibitor drug, with conventional chemotherapy to improve NSCLC treatment. Methods: The effect of pentoxifylline in the expression levels of P-glycoprotein (P-gp), CHI3L1 and its main downstream proteins, as well as on cell death, cell cycle profile, and P-gp activity was studied in two pairs of sensitive and MDR counterpart NSCLC cell lines (NCI-H460/NCI-H460/R and A549/A549-CDR2). Association studies between CHI3L1 gene expression and NSCLC patients' survival were performed using The Cancer Genome Atlas (TCGA) analysis. The sensitizing effect of pentoxifylline to different drug regimens was evaluated in both sensitive and MDR NSCLC cell lines. The cytotoxicity of the drug combinations was assessed in MCF10A non-tumorigenic cells. Results: Pentoxifylline slightly decreased the expression levels of CHI3L1, β-catenin and signal transducer and activator of transcription 3 (STAT3), and caused a significant increase in the G1 phase of the cell cycle in both pairs of NSCLC cell lines. A significant increase in the % of cell death was observed in the sensitive NCI-H460 cell line. TCGA analysis revealed that high levels of CHI3L1 are associated with low overall survival (OS) in NSCLC patients treated with vinorelbine. Moreover, pentoxifylline sensitized both pairs of sensitive and MDR NSCLC cell lines to the different drug regimens, without causing significant toxicity to non-tumorigenic cells. Conclusion: This study suggests the possibility of combining pentoxifylline with chemotherapy to increase NSCLC therapeutic response, even in cases of MDR.

Keywords:  Chitinase 3-like-1; combined therapies; drug repurposing; multidrug resistance; non-small cell lung cancer; pentoxifylline

DOI:  https://doi.org/10.20517/cdr.2024.04
J Bone Miner Res. 2024 Jun 06. pii: zjae085. [Epub ahead of print]

Hdac3-deficiency increases senescence-associated distention of satellite DNA and telomere-associated foci in osteoprogenitor cells.

Dongwook Yeo, Elizabeth L Zars Fisher, Sundeep Khosla, Joshua N Farr, Jennifer J Westendorf.

  Histone deacetylase 3 (Hdac3) is an epigenetic regulator of gene expression and interacts with skeletal transcription factors such as Runx2. We previously reported that conditional deletion of Hdac3 in Osterix-Cre recombinase-expressing osteoprogenitor cells (Hdac3 CKOOsx) caused osteopenia and increased marrow adiposity, both hallmarks of skeletal aging. We also showed that Runx2+ cells within osteogenic cultures of Hdac3-depleted bone marrow stromal cells (BMSCs) contain lipid droplets (LDs). Cellular senescence, a non-proliferative metabolically active state, is associated with increased marrow adiposity, bone loss and aging. In this study, we sought to determine if Hdac3 depleted Runx2+ pre-osteoblasts from young mice exhibit chromatin changes associated with early cellular senescence and how these events correlate with the appearance of LDs. We first confirmed that BMSCs from Hdac3 CKOOsx mice have more Runx2 + LD+ cells compared to controls under osteogenic conditions. We then measured senescence-associated distention of satellite DNA (SADS) and telomere-associated foci (TAFs) in Hdac3 CKOOsx and control BMSCs. In situ, Runx2+ cells contained more SADs per nuclei in Hdac3 CKOOsx femora than in controls. Runx2+ BMSCs from Hdac3 CKOOsx mice also contained more SADS and TAFs per nuclei than Runx2+ cells from age-matched control mice in vitro. SADs and TAFs were present at similar levels in Runx2 + LD+ cells and Runx2 + LD- cells from Hdac3 CKOOsx mice. Hdac inhibitors also increased the number of SADS in Runx2 + LD+ and Runx2 + LD- wildtype BMSCs. Senolytics reduced viable cell numbers in Hdac3 CKOOsx BMSC cultures. These data demonstrate that depletion of Hdac3 in osteochondral progenitor cells triggers LD formation and early events in cellular senescence in Runx2+ BMSCs through mutually exclusive mechanisms.

Keywords:  Hdac3; Lipid droplets; RGFP966; Runx2; SAHA; Senescence; Senolytics

DOI:  https://doi.org/10.1093/jbmr/zjae085
Sci China Life Sci. 2024 Jun;67(6): 1089-1105

Di- and tri-methylation of histone H3K36 play distinct roles in DNA double-strand break repair.

Runfa Chen, Meng-Jie Zhao, Yu-Min Li, Ao-Hui Liu, Ru-Xin Wang, Yu-Chao Mei, Xuefeng Chen, Hai-Ning Du.

  Histone H3 Lys36 (H3K36) methylation and its associated modifiers are crucial for DNA double-strand break (DSB) repair, but the mechanism governing whether and how different H3K36 methylation forms impact repair pathways is unclear. Here, we unveil the distinct roles of H3K36 dimethylation (H3K36me2) and H3K36 trimethylation (H3K36me3) in DSB repair via non-homologous end joining (NHEJ) or homologous recombination (HR). Yeast cells lacking H3K36me2 or H3K36me3 exhibit reduced NHEJ or HR efficiency. yKu70 and Rfa1 bind H3K36me2- or H3K36me3-modified peptides and chromatin, respectively. Disrupting these interactions impairs yKu70 and Rfa1 recruitment to damaged H3K36me2- or H3K36me3-rich loci, increasing DNA damage sensitivity and decreasing repair efficiency. Conversely, H3K36me2-enriched intergenic regions and H3K36me3-enriched gene bodies independently recruit yKu70 or Rfa1 under DSB stress. Importantly, human KU70 and RPA1, the homologs of yKu70 and Rfa1, exclusively associate with H3K36me2 and H3K36me3 in a conserved manner. These findings provide valuable insights into how H3K36me2 and H3K36me3 regulate distinct DSB repair pathways, highlighting H3K36 methylation as a critical element in the choice of DSB repair pathway.

Keywords:  Ku70; RPA; histone H3K36 methylation; homologous recombination; non-homologous end joining

DOI:  https://doi.org/10.1007/s11427-024-2543-9
Transl Oncol. 2024 Jun 05. pii: S1936-5233(24)00141-4. [Epub ahead of print]46 102014

The PRC2 complex epigenetically silences GATA4 to suppress cellular senescence and promote the progression of breast cancer.

Wenqian Yu, Xiaona Lin, Shuai Leng, Yiming Hou, Zhiqiao Dang, Shishan Xue, Na Li, Fengquan Zhang.

   BACKGROUND: The transcription factor GATA4 is pivotal in cancer development but is often silenced through mechanisms like DNA methylation and histone modifications. This silencing suppresses the transcriptional activity of GATA4, disrupting its normal functions and promoting cancer progression. However, the precise molecular mechanisms and implications of GATA4 silencing in tumorigenesis remain unclear. Here, we aim to elucidate the mechanisms underlying GATA4 silencing and explore its role in breast cancer progression and its potential as a therapeutic target.
METHODS: The GATA4-breast cancer prognosis link was explored via bioinformatics analyses, with GATA4 expression measured in breast tissues. Functional gain/loss experiments were performed to gauge GATA4's impact on breast cancer cell malignancy. GATA4-PRC2 complex interaction was analyzed using silver staining and mass spectrometry. Chromatin immunoprecipitation, coupled with high-throughput sequencing, was used to identify GATA4-regulated downstream target genes. The in vitro findings were validated in an in situ breast cancer xenograft mouse model.
RESULTS: GATA4 mutation and different breast cancer subtypes were correlated, suggesting its involvement in disease progression. GATA4 suppressed cell proliferation, invasion, and migration while inducing apoptosis and senescence in breast cancer cells. The GATA4-PRC2 complex interaction silenced GATA4 expression, which altered the regulation of FAS, a GATA4 downstream gene. In vivo experiments verified that GATA4 inhibits tumor growth, suggesting its regulatory function in tumorigenesis.
CONCLUSIONS: This comprehensive study highlights the epigenetic regulation of GATA4 and its impact on breast cancer development, highlighting the PRC2-GATA4-FAS pathway as a potential target for therapeutic interventions in breast cancers.

Keywords:  Breast cancer; Cell senescence; Epigenetic regulation; GATA4; PRC2 complex

DOI:  https://doi.org/10.1016/j.tranon.2024.102014