bims-ectoca 2023-04-16 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023‒04‒16
eight papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Oncogenic super-enhancers in cancer: mechanisms and therapeutic targets.
Microtubule Assists Actomyosin to Regulate Cell Nuclear Mechanics and Chromatin Accessibility.
Sirtuin1-p53: a potential axis for cancer therapy.
Cell-to-cell variability in Myc dynamics drives transcriptional heterogeneity in cancer cells.
Single-cell RNA-seq reveals intratumoral heterogeneity in osteosarcoma patients: A review.
Serotonin acts through YAP to promote cell proliferation: mechanism and implication in colorectal cancer progression.
Tumor Microenvironmental Cytokines Drive NSCLC Cell Aggressiveness and Drug-Resistance via YAP-Mediated Autophagy.
The engagement of histone lysine methyltransferases with nucleosomes: structural basis, regulatory mechanisms, and therapeutic implications.

Cancer Metastasis Rev. 2023 Apr 14.

Oncogenic super-enhancers in cancer: mechanisms and therapeutic targets.

Megan Bacabac, Wei Xu.

  Activation of oncogenes to sustain proliferative signaling and initiate metastasis are important hallmarks of cancer. Oncogenes are amplified or overexpressed in cancer cells and overexpression is often controlled at the level of transcription. Gene expression is tightly controlled by many cis-regulatory elements and trans-acting factors. Large clusters of enhancers known as "super-enhancers" drive robust expression of cell-fate determining transcription factors in cell identity. Cancer cells can take advantage of super-enhancers and become transcriptionally addicted to them leading to tumorigenesis and metastasis. Additionally, the cis-regulatory landscape of cancer includes aberrant super-enhancers that are not present in normal cells. The landscape of super-enhancers in cancer is characterized by high levels of histone H3K27 acetylation and bromodomain-containing protein 4 (BRD4), and Mediator complex. These chromatin features facilitate the identification of cancer type-specific and cell-type-specific super-enhancers that control the expression of important oncogenes to stimulate their growth. Disruption of super-enhancers via inhibiting BRD4 or other epigenetic proteins is a potential therapeutic option. Here, we will describe the discovery of super-enhancers and their unique characteristics compared to typical enhancers. Then, we will highlight how super-enhancer-associated genes contribute to cancer progression in different solid tumor types. Lastly, we will cover therapeutic targets and their epigenetic modulators.

Keywords:  BRD4; Enhancer reprogramming; Epigenetic modulators; Mediator; Metastasis; Super-enhancers

DOI:  https://doi.org/10.1007/s10555-023-10103-4
Research (Wash D C). 2023 ;6 0054

Microtubule Assists Actomyosin to Regulate Cell Nuclear Mechanics and Chromatin Accessibility.

Jiwen Geng, Zhefeng Kang, Qian Sun, Man Zhang, Peng Wang, Yupei Li, Jiameng Li, Baihai Su, Qiang Wei.

Cellular behaviors and functions can be regulated by mechanical cues from microenvironments, which are transmitted to nucleus through the physical connections of cytoskeletons in the cells. How these physical connections determine transcriptional activity were not clearly known. The actomyosin, which generates intracellular traction force, has been recognized to control the nuclear morphology. Here, we have revealed that microtubule, the stiffest cytoskeleton, is also involved in the process of nuclear morphology alteration. The microtubule negatively regulates the actomyosin-induced nuclear invaginations but not the nuclear wrinkles. Moreover, these nuclear shape changes are proven to mediate the chromatin remodeling, which essentially mediates cell gene expression and phenotype determination. The actomyosin disruption leads to the loss of chromatin accessibility, which can be partly recovered by microtubule interference through nuclear shape control. This finding answers the question of how mechanical cues regulate chromatin accessibility and cell behaviors. It also provides new insights into cell mechanotransduction and nuclear mechanics.

DOI: https://doi.org/10.34133/research.0054
Biochem Pharmacol. 2023 Apr 08. pii: S0006-2952(23)00134-X. [Epub ahead of print] 115543

Sirtuin1-p53: a potential axis for cancer therapy.

Jia-Yi Yin, Xin-Tong Lu, Meng-Ling Hou, Ting Cao, Zhen Tian.

  Sirtuin1 (SIRT1) is a conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that plays key roles in a range of cellular events, including the maintenance of genome stability, gene regulation, cell proliferation, and apoptosis. P53 is one of the most studied tumor suppressors and the first identified non-histone target of SIRT1. SIRT1 deacetylates p53 in a NAD+-dependent manner and inhibits its transcriptional activity, thus exerting action on a series of pathways related to tissue homeostasis and various pathological states. The SIRT1-p53 axis is thought to play a central role in tumorigenesis. Although SIRT1 was initially identified as a tumor promoter, evidence now indicates that SIRT1 may also act as a tumor suppressor. This seemingly contradictory evidence indicates that the functionality of SIRT1 may be dictated by different cell types and intracellular localization patterns. In this review, we summarize recent evidence relating to the interactions between SIRT1 and p53 and discuss the relative roles of these two molecules with regards to cancer-associated cellular events. We also provide an overview of current knowledge of SIRT1-p53 signaling in tumorigenesis. Given the vital role of the SIRT1-p53 pathway, targeting this axis may provide promising strategies for the treatment of cancer.

Keywords:  SIRT1; apoptosis; cancer; deacetylates; p53

DOI:  https://doi.org/10.1016/j.bcp.2023.115543
Cell Rep. 2023 Apr 13. pii: S2211-1247(23)00412-6. [Epub ahead of print]42(4): 112401

Cell-to-cell variability in Myc dynamics drives transcriptional heterogeneity in cancer cells.

Chad Liu, Takamasa Kudo, Xin Ye, Karen Gascoigne.

  Cell-to-cell heterogeneity is vital for tumor evolution and survival. How cancer cells achieve and exploit this heterogeneity remains an active area of research. Here, we identify c-Myc as a highly heterogeneously expressed transcription factor and an orchestrator of transcriptional and phenotypic diversity in cancer cells. By monitoring endogenous c-Myc protein in individual living cells, we report the surprising pulsatile nature of c-Myc expression and the extensive cell-to-cell variability in its dynamics. We further show that heterogeneity in c-Myc dynamics leads to variable target gene transcription and that timing of c-Myc expression predicts cell-cycle progression rates and drug sensitivities. Together, our data advocate for a model in which cancer cells increase the heterogeneity of functionally diverse transcription factors such as c-Myc to rapidly survey transcriptional landscapes and survive stress.

Keywords:  CP: Cancer; CP: Cell biology; Myc; cancer; cell-to-cell heterogeneity; gene expression; transcription

DOI:  https://doi.org/10.1016/j.celrep.2023.112401
J Bone Oncol. 2023 Apr;39 100475

Single-cell RNA-seq reveals intratumoral heterogeneity in osteosarcoma patients: A review.

Dylan D Thomas, Ryan A Lacinski, Brock A Lindsey.

  While primary bone malignancies make up just 0.2% of all cancers, osteosarcoma (OS) is the third most common cancer in adolescents. Due to its highly complex and heterogeneous tumor microenvironment (TME), OS has proven difficult to treat. There has been little to no improvement in therapy for this disease over the last 40 years. Even the recent success of immunotherapies in other blood-borne and solid malignancies has not translated to OS. With frequent recurrence and lung metastases continuing to pose a challenge in the clinic, recent advancements in molecular profiling, such as single-cell RNA sequencing (scRNA-seq), have proven useful in identifying novel biomarkers of OS tumors while providing new insight into this TME that could potentially lead to new therapeutic options. This review combines the analyses of over 150,000 cells from 18 lesions ranging from primary, recurrent, and metastatic OS lesions, revealing distinct cellular populations and gene signatures that exist between them. Here, we detail these previous findings and ultimately convey the intratumoral heterogeneity that exists within OS tumor specimens.

Keywords:  Intratumoral heterogeneity; Metastasis; Microenvironment; Osteosarcoma; Recurrence; Sequencing; Single-cell

DOI:  https://doi.org/10.1016/j.jbo.2023.100475
Cell Commun Signal. 2023 04 12. 21(1): 75

Serotonin acts through YAP to promote cell proliferation: mechanism and implication in colorectal cancer progression.

Huangfei Yu, Tianyin Qu, Jinlan Yang, Qing Dai.

  Serotonin, also known as 5-hydroxytryptamine (5-HT), is a key messenger that mediates several central and peripheral functions in the human body. Emerging evidence indicates that serotonin is critical in tumorigenesis, but its role in colorectal cancer remains elusive. Herein, we report that serotonin transporter (SERT) transports serotonin into colorectal cancer cells, enhancing Yes-associated protein (YAP) expression and promoting in vitro and in vivo colon cancer cell growth. Once within the cells, transglutaminase 2 (TG2) mediates RhoA serotonylated and activates RhoA-ROCK1/2 signalling to upregulate YAP expression in SW480 and SW1116 cells. Blocking SERT with citalopram reversed the serotonin-induced YAP expression and cell proliferation, inhibiting serotonin's effects on tumour formation in mice. Moreover, SERT expression was correlated with YAP in pathological human colorectal cancer samples and the levels of 5-HT were highly significant in the serum of patients with colorectal cancer. Together, our findings suggested that serotonin enters cells via SERT to activate RhoA/ROCK/YAP signalling to promote colon cancer carcinogenesis. Consequently, targeting serotonin-SERT-YAP axis may be a potential therapeutic strategy for colorectal cancer. Video abstract.

Keywords:  Colorectal cancer; Serotonin; Serotonin transporter; Serotonylation; YAP

DOI:  https://doi.org/10.1186/s12964-023-01096-2
Cells. 2023 Mar 30. pii: 1048. [Epub ahead of print]12(7):

Tumor Microenvironmental Cytokines Drive NSCLC Cell Aggressiveness and Drug-Resistance via YAP-Mediated Autophagy.

Paola Matarrese, Rosa Vona, Barbara Ascione, Camilla Cittadini, Annalisa Tocci, Anna Maria Mileo.

  Dynamic reciprocity between cellular components of the tumor microenvironment and tumor cells occurs primarily through the interaction of soluble signals, i.e., cytokines produced by stromal cells to support cancer initiation and progression by regulating cell survival, differentiation and immune cell functionality, as well as cell migration and death. In the present study, we focused on the analysis of the functional response of non-small cell lung cancer cell lines elicited by the treatment with some crucial stromal factors which, at least in part, mimic the stimulus exerted in vivo on tumor cells by microenvironmental components. Our molecular and functional results highlight the role played by the autophagic machinery in the cellular response in terms of the invasive capacity, stemness and drug resistance of two non-small lung cancer cell lines treated with stromal cytokines, also highlighting the emerging role of the YAP pathway in the mutual and dynamic crosstalk between tumor cells and tumor microenvironment elements. The results of this study provide new insights into the YAP-mediated autophagic mechanism elicited by microenvironmental cytokines on non-small cell lung cancer cell lines and may suggest new potential strategies for future cancer therapeutic interventions.

Keywords:  autophagy; cancer progression; cytokines; drug-resistance; epithelial-mesenchymal transition (EMT); invasion; microenvironment; non-small cell lung cancer (NSCLC)

DOI:  https://doi.org/10.3390/cells12071048
Protein Cell. 2023 Apr 13. 14(3): 165-179

The engagement of histone lysine methyltransferases with nucleosomes: structural basis, regulatory mechanisms, and therapeutic implications.

Yanjing Li, Kexue Ge, Tingting Li, Run Cai, Yong Chen.

  Histone lysine methyltransferases (HKMTs) deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression. The structures and functions of HKMTs have been extensively investigated in recent decades, significantly advancing our understanding of the dynamic regulation of histone methylation. Here, we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes (H3K4, H3K27, H3K36, H3K79, and H4K20 methyltransferases), with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs. These structural studies inform HKMTs' roles in tumorigenesis and provide the foundations for developing new therapeutic approaches targeting HKMTs in cancers.

Keywords:  cryo-EM structures; epigenetics; histone methylation; histone methyltransferases; nucleosome; tumorigenesis

DOI:  https://doi.org/10.1093/procel/pwac032