bims-ectoca 2023-02-05 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023‒02‒05
seven papers selected by
Ankita Daiya
BITS Pilani

Therapeutic targeting of TEAD transcription factors in cancer.
Could senescence phenotypes strike the balance to promote tumor dormancy?
Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis.
Beyond expression: role of phosphorylated residues of EZH2 in lineage plasticity in prostate cancer.
Mitochondrial dysfunction and chromatin changes with autophagy-mediated survival in doxorubicin resistant cancer cell lines.
YAP and TAZ couple osteoblast precursor mobilization to angiogenesis and mechanoregulated bone development.
Cell Response to Mechanical Microenvironment Cues via Rho Signaling: From Mechanobiology to Mechanomedicine.

Trends Biochem Sci. 2023 Jan 26. pii: S0968-0004(22)00333-4. [Epub ahead of print]

Therapeutic targeting of TEAD transcription factors in cancer.

Ajaybabu V Pobbati, Ramesh Kumar, Brian P Rubin, Wanjin Hong.

  The Hippo signaling pathway inhibits the activity of the oncogenic YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex. In cancers, inactivating mutations in upstream Hippo components and/or enhanced activity of YAP/TAZ and TEAD have been observed. The activity of this transcriptional complex can be effectively inhibited by targeting the TEAD family of transcription factors. The development of TEAD inhibitors has been driven by the discovery that TEAD has druggable hydrophobic pockets, and is currently at the clinical development stage. Three small molecule TEAD inhibitors are currently being tested in Phase I clinical trials. In this review, we highlight the role of TEADs in cancer, discuss various avenues through which TEAD activity can be inhibited, and outline the opportunities for the administration of TEAD inhibitors.

Keywords:  Hippo signaling; TEAD; YAP; cancer therapy; drug discovery

DOI:  https://doi.org/10.1016/j.tibs.2022.12.005
Cancer Metastasis Rev. 2023 Feb 03.

Could senescence phenotypes strike the balance to promote tumor dormancy?

Fang-Yen Chiu, Raegan M Kvadas, Zeinab Mheidly, Ashkan Shahbandi, James G Jackson.

  After treatment and surgery, patient tumors can initially respond followed by a rapid relapse, or respond well and seemingly be cured, but then recur years or decades later. The state of surviving cancer cells during the long, undetected period is termed dormancy. By definition, the dormant tumor cells do not proliferate to create a mass that is detectable or symptomatic, but also never die. An intrinsic state and microenvironment that are inhospitable to the tumor would bias toward cell death and complete eradication, while conditions that favor the tumor would enable growth and relapse. In neither case would clinical dormancy be observed. Normal cells and tumor cells can enter a state of cellular senescence after stress such as that caused by cancer therapy. Senescence is characterized by a stable cell cycle arrest mediated by chromatin modifications that cause gene expression changes and a secretory phenotype involving many cytokines and chemokines. Senescent cell phenotypes have been shown to be both tumor promoting and tumor suppressive. The balance of these opposing forces presents an attractive model to explain tumor dormancy: phenotypes of stable arrest and immune suppression could promote survival, while reversible epigenetic programs combined with cytokines and growth factors that promote angiogenesis, survival, and proliferation could initiate the emergence from dormancy. In this review, we examine the phenotypes that have been characterized in different normal and cancer cells made senescent by various stresses and how these might explain the characteristics of tumor dormancy.

Keywords:  Angiogenesis; Breast cancer; Cellular senescence; Chromatin; Immune evasion; Tumor dormancy; p53

DOI:  https://doi.org/10.1007/s10555-023-10089-z
Nat Cell Biol. 2023 Feb 02.

Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis.

Xiaohua Hu, Xiaoping Wu, Kalen Berry, Chuntao Zhao, Dazhuan Xin, Sean Ogurek, Xuezhao Liu, Liguo Zhang, Zaili Luo, Masahide Sakabe, Joanna Trubicka, Maria Łastowska, Frank Szulzewsky, Eric C Holland, Lindsay Lee, Ming Hu, Mei Xin, Q Richard Lu.

Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.

DOI: https://doi.org/10.1038/s41556-022-01069-6
Endocrinology. 2023 Jan 30. pii: bqad023. [Epub ahead of print]

Beyond expression: role of phosphorylated residues of EZH2 in lineage plasticity in prostate cancer.

Shaghayegh Nouruzi, Nakisa Tabrizian, Amina Zoubeidi.

  Despite the development of effective targeted therapies and a significant understanding of carcinogenesis and cancer progression, treatment resistance is a major obstacle in achieving durable long-term control in many types of cancers. Emerging evidence supports that non-genetic mechanisms could play an underappreciated role in therapy resistance. These mechanisms include phenotypic plasticity, which is recognized as one of the hallmarks of cancer and translates to epigenetic and transcriptional control of gene expression. Alterations in the expression and activity of the epigenetic modifier enhancer of zeste homolog 2 (EZH2) support prostate cancer lineage plasticity and progression. EZH2 expression and activity is elevated in castration-resistant prostate cancer treated with androgen receptor (AR) pathway inhibitors and in treatment-resistant prostate cancer. Moreover, 17 known residues of EZH2 are phosphorylated on by multiple kinases that modulate its activity, localization, stability, and polycomb repressive complex (PRC2) assembly. In this review, we explore the contribution of EZH2 phosphorylation in regulating canonical PRC2 in a methylation-dependent manner as an epigenetic repressor and in a non-canonical manner independent of PRC2 as a transcription activator. Apart from the contribution of EZH2 phosphorylation at serine 21, threonine 350, and threonine 311 in prostate cancer progression and treatment resistance, we discuss how other EZH2 phosphorylated residues with unknown functions could contribute to prostate cancer based on their upstream regulators and potential therapeutic utility.

Keywords:  EZH2; cancer; phosphorylation; polycomb repressive complex 2; prostate

DOI:  https://doi.org/10.1210/endocr/bqad023
Biochem Biophys Res Commun. 2023 Jan 27. pii: S0006-291X(23)00126-2. [Epub ahead of print]648 1-10

Mitochondrial dysfunction and chromatin changes with autophagy-mediated survival in doxorubicin resistant cancer cell lines.

Abhiram Natu, Aditi Pedgaonkar, Sanjay Gupta.

  Acquired chemoresistance against doxorubicin remains an obstacle in long-term treatment. The comprehensive molecular mechanism underlying the acquirement of doxorubicin resistance has not been reported. The objective of the present study is to understand the survival strategies and investigate alternate treatments for doxorubicin-resistant cervical and liver cancer cells. In this study, doxorubicin-resistant sublines were established by continuous incremental exposure of the drug to parental cervical and liver cancer cells. The transcriptome data in drug-resistant model revealed downregulated energy production pathways like glycolysis, oxidative phosphorylation, and mTOR signalling. This resulted in slow proliferation and altered mitochondrial changes in doxorubicin-resistant cells. The altered metabolic state of the resistant cells was associated with hypo-acetylation of chromatin. Pre-treatment with HDACi sensitized the drug-resistant cells to doxorubicin by increased drug accumulation in the cells, thereby leading to apoptosis. Additionally, we demonstrated that autophagy gets activated in doxorubicin-resistant cervical and liver cancer cells. Autophagy acts as pro-survival mechanism in resistant cells, as inhibition of autophagy leads to cell death. In conclusion, the data highlights survival ability of resistant cells with mitochondrial dysfunction, altered chromatin state, and pro-survival autophagy. The study proposes targeting chromatin alteration with the combinatorial treatment of HDACi with doxorubicin or survival mechanism through autophagy inhibitor against doxorubicin-resistant cancer phenotype.

Keywords:  Autophagy; Cancer; Doxorubicin; Hypoacetylation; Mitochondria

DOI:  https://doi.org/10.1016/j.bbrc.2023.01.081
bioRxiv. 2023 Jan 21. pii: 2023.01.20.524918. [Epub ahead of print]

YAP and TAZ couple osteoblast precursor mobilization to angiogenesis and mechanoregulated bone development.

Joseph M Collins, Annemarie Lang, Cristian Parisi, Yasaman Moharrer, Madhura P Nijsure, Jong Hyun Thomas Kim, Greg L Szeto, Ling Qin, Riccardo L Gottardi, Nathanial A Dyment, Niamh C Nowlan, Joel D Boerckel.

Endochondral ossification requires coordinated mobilization of osteoblast precursors with blood vessels. During adult bone homeostasis, vessel adjacent osteoblast precursors respond to and are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Previously, we found that deletion of the mechanoresponsive transcriptional regulators, YAP and TAZ, from Osterix-expressing osteoblast precursors and their progeny caused perinatal lethality. Here, we show that embryonic YAP/TAZ signaling couples vessel-associated osteoblast precursor mobilization to angiogenesis in developing long bones. Osterix-conditional YAP/TAZ deletion impaired endochondral ossification in the primary ossification center but not intramembranous osteogenesis in the bone collar. Single-cell RNA sequencing revealed YAP/TAZ regulation of the angiogenic chemokine, Cxcl12, which was expressed uniquely in vessel-associated osteoblast precursors. YAP/TAZ signaling spatially coupled osteoblast precursors to blood vessels and regulated vascular morphogenesis and vessel barrier function. Further, YAP/TAZ signaling regulated vascular loop morphogenesis at the chondro-osseous junction to control hypertrophic growth plate remodeling. In human cells, mesenchymal stromal cell co-culture promoted 3D vascular network formation, which was impaired by stromal cell YAP/TAZ depletion, but rescued by recombinant CXCL12 treatment. Lastly, YAP and TAZ mediated mechanotransduction for load-induced osteogenesis in embryonic bone.

DOI: https://doi.org/10.1101/2023.01.20.524918
Acta Biomater. 2023 Jan 27. pii: S1742-7061(23)00043-0. [Epub ahead of print]

Cell Response to Mechanical Microenvironment Cues via Rho Signaling: From Mechanobiology to Mechanomedicine.

Ning Xie, Cailan Xiao, Qiuai Shu, Bo Cheng, Ziwei Wang, Runxin Xue, Zhang Wen, Jinhai Wang, Haitao Shi, Daiming Fan, Na Liu, Feng Xu.

  Mechanical cues in the cell microenvironment such as those from extracellular matrix properties, stretching, compression and shear stress, play a critical role in maintaining homeostasis. Upon sensing mechanical stimuli, cells can translate these external forces into intracellular biochemical signals to regulate their cellular behaviors, but the specific mechanisms of mechanotransduction at the molecular level remain elusive. As a subfamily of the Ras superfamily, Rho GTPases have been recognized as key intracellular mechanotransduction mediators that can regulate multiple cell activities such as proliferation, migration and differentiation as well as biological processes such as cytoskeletal dynamics, metabolism, and organ development. However, the upstream mechanosensors for Rho proteins and downstream effectors that respond to Rho signal activation have not been well illustrated. Moreover, Rho-mediated mechanical signals in previous studies are highly context-dependent. In this review, we systematically summarize the types of mechanical cues in the cell microenvironment and provide recent advances on the roles of the Rho-based mechanotransduction in various cell activities, physiological processes and diseases. Comprehensive insights into the mechanical roles of Rho GTPase partners would open a new paradigm of mechanomedicine for a variety of diseases. STATEMENT OF SIGNIFICANCE: In this review, we highlight the critical role of Rho GTPases as signal mediators to respond to physical cues in microenvironment. This article will add a distinct contribution to this set of knowledge by intensively addressing the relationship between Rho signaling and mechanobiology/mechanotransduction/mechanomedcine. This topic has not been discussed by the journal, nor has it yet been developed by the field. The comprehensive picture that will develop, from molecular mechanisms and engineering methods to disease treatment strategies, represents an important and distinct contribution to the field. We hope that this review would help researchers in various fields, especially clinicians, oncologists and bioengineers, who study Rho signal pathway and mechanobiology/mechanotransduction, understand the critical role of Rho GTPase in mechanotransduction.

Keywords:  Rho GTPases; cell compression and shear stress; cell stretching; extracellular matrix properties; mechanomedicine; mechanotransduction

DOI:  https://doi.org/10.1016/j.actbio.2023.01.039