Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence

Wu, Zhong; Zhang, Jin; Zhang, Xiaoyang; Zhang, Zhouwei; Xie, Yingtian; Liu, Jie Bin; Ho, Zandra V.; Panda, Arpit; Qiu, Xintao; Cejas, Paloma; Cañadas, Israel; Akarca, Fahire G.; McFarland, James M.; Nagaraja, Ankur K.; Goss, Louisa B; Kesten, Nikolas; Si, Longlong; Lim, Klothilda; Li, Yanli; Zhang, Yanxi; Baek, Ji Yeon; Liu, Yang; Patil, Deepa T.; Katz, Jonathan P.; Hai, Josephine; Bao, Chunyang; Stachler, Matthew D.; Qi, Jun; Ishizuka, Jeffrey J.; Nakagawa, Hiroshi; Rustgi, Anil K.; Wong, Kwok‐Kin; Meyerson, Matthew; Barbie, David A.; Brown, Myles; Long, Henry W.; Bass, Adam J.

doi:10.1038/s41588-021-00859-2

Cited by 58 publications

(43 citation statements)

References 82 publications

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“…The tumorigenesis and progression of ESCC correlate with multiple mechanisms and biological processes, including dysregulation of tumor immune microenvironment, activation of kinases signaling, as well as metabolic disorders ( 31 – 33 ). Among them, epigenetic remodeling has been well documented and considered to be essential molecular features of tumorigenesis ( 34 , 35 ). Here, we screened the prognostic epigenetic regulators in TCGA-ESCC and identified KDM4D as a tumor suppressor via low-throughput validations.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulator KDM4D Restricts Tumorigenesis via Modulating SYVN1/HMGB1 Ubiquitination Axis in Esophageal Squamous Cell Carcinoma

et al. 2021

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BackgroundIncreasing researches have been reported that epigenetic alterations play critical roles in ESCC development. However, the role of the histone demethylase KDM4D in ESCC tumorigenesis is poorly investigated. This study aims to discover the underlying mechanisms between KDM4D and ESCC progression.MethodsCCK-8 assays, clone formation assay and soft-agar assays were performed to assess cell proliferation. Transwell assay was utilized to assess cell migration efficiency, while sphere formation assay was used to evaluate the cell self-renewal ability. Bioinformatic analysis was conducted to identify prognostic factors and predict the potential E3 ubiquitin ligases. In vitro ubiquitination assay was conducted to confirm the regulations between SYVN1 and HMGB1. The mRNA levels or protein levels of genes were detected by real-time PCR and western blot analysis. In vivo tumor xenograft models were used to determine whether the HMGB1 inhibition affected the malignant features of ESCC cells.ResultEpigenome screening and low-throughput validations highlighted that KDM4D is a tumor suppressor in ESCC. KDM4D expressed lowly in tumors that predicts poor prognosis. KDM4D deficiency significantly enhanced tumor growth, migration and stemness. Mechanistically, KDM4D transcriptionally activates SYVN1 expressions via H3K9me3 demethylation at the promoter region, thereby triggering the ubiquitin-dependent degradation of HMGB1. Low KDM4D depended on accumulated HMGB1 to drive ESCC progression and aggressiveness. Targeting HMGB1 (Glycyrrhizin) could remarkably suppress ESCC tumor growth in vitro and in vivo, especially in KDM4D-deficient cells.ConclusionsWe systematically identified KDM4D/SYVN1/HMGB1 axis in ESCC progression, proving novel biomarkers and potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Regulator KDM4D Restricts Tumorigenesis via Modulating SYVN1/HMGB1 Ubiquitination Axis in Esophageal Squamous Cell Carcinoma

et al. 2021

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“…As dominant of transposable elements, the amplification of LTRs is considered to be harmful to genome stability ( 1 ), therefore, in most situation, LTRs are silenced by various repressive epigenetic mechanisms, such as DNA methylation, H3K9me3, PRC1/2 complex and piwi/piRNA pathway ( 2–6 ). LTRs are involved in many pathological processes, such as neurodegenerative diseases ( 7–9 ), cancer progression ( 10 , 11 ) and inflammatory bowel disease ( 12 ). In addition, LTRs are also involved in normal biological processes, illustrated by the recent report that species-specific LTRs shape its specific early embryonic development process and are essential for embryonic development ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Active endogenous retroviral elements in human pluripotent stem cells play a role in regulating host gene expression

Zhang

Zheng

et al. 2022

Nucleic Acids Research

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Human endogenous retroviruses, also called LTR elements, can be bound by transcription factors and marked by different histone modifications in different biological contexts. Recently, individual LTR or certain subclasses of LTRs such as LTR7/HERVH and LTR5_Hs/HERVK families have been identified as cis-regulatory elements. However, there are still many LTR elements with unknown functions. Here, we dissected the landscape of histone modifications and regulatory map of LTRs by integrating 98 ChIP-seq data in human embryonic stem cells (ESCs), and annotated the active LTRs enriching enhancer/promoter-related histone marks. Notably, we found that MER57E3 functionally acted as proximal regulatory element to activate respective ZNF gene. Additionally, HERVK transcript could mainly function in nucleus to activate the adjacent genes. Since LTR5_Hs/LTR5 was bound by many early embryo-specific transcription factors, we further investigated the expression dynamics in different pluripotent states. LTR5_Hs/LTR5/HERVK exhibited higher expression level in naïve ESCs and extended pluripotent stem cells (EPSCs). Functionally, the LTR5_Hs/LTR5 with high activity could serve as a distal enhancer to regulate the host genes. Ultimately, our study not only provides a comprehensive regulatory map of LTRs in human ESCs, but also explores the regulatory models of MER57E3 and LTR5_Hs/LTR5 in host genome.

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“…The same caveat is applied to the same group's another study in esophageal squamous cell carcinoma, where they found that Trp53/Cdkn2a loss synergizes with transcription factor Sox2 to promote chromatin remodeling, enhance Stat3 functions, activate endogenous retroviruses, and induce double-stranded RNA expression and dependence of RNA editing enzyme ADAR1 (Wu et al, 2021). Implication of this study could inform new strategies to develop therapies against cancers that display similar characteristics (p53/ARF co-inactivation and ADAR1 dependency), such as TNBC (Forys et al, 2014;Kung et al, 2021).…”

Section: Co-inactivation Of P53 and Arfmentioning

confidence: 97%

It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

Kung

Weber

2022

Front. Cell Dev. Biol.

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Anti-tumorigenic mechanisms mediated by the tumor suppressor p53, upon oncogenic stresses, are our bodies’ greatest weapons to battle against cancer onset and development. Consequently, factors that possess significant p53-regulating activities have been subjects of serious interest from the cancer research community. Among them, MDM2 and ARF are considered the most influential p53 regulators due to their abilities to inhibit and activate p53 functions, respectively. MDM2 inhibits p53 by promoting ubiquitination and proteasome-mediated degradation of p53, while ARF activates p53 by physically interacting with MDM2 to block its access to p53. This conventional understanding of p53-MDM2-ARF functional triangle have guided the direction of p53 research, as well as the development of p53-based therapeutic strategies for the last 30 years. Our increasing knowledge of this triangle during this time, especially through identification of p53-independent functions of MDM2 and ARF, have uncovered many under-appreciated molecular mechanisms connecting these three proteins. Through recognizing both antagonizing and synergizing relationships among them, our consideration for harnessing these relationships to develop effective cancer therapies needs an update accordingly. In this review, we will re-visit the conventional wisdom regarding p53-MDM2-ARF tumor-regulating mechanisms, highlight impactful studies contributing to the modern look of their relationships, and summarize ongoing efforts to target this pathway for effective cancer treatments. A refreshed appreciation of p53-MDM2-ARF network can bring innovative approaches to develop new generations of genetically-informed and clinically-effective cancer therapies.

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Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence

Cited by 58 publications

References 82 publications

Epigenetic Regulator KDM4D Restricts Tumorigenesis via Modulating SYVN1/HMGB1 Ubiquitination Axis in Esophageal Squamous Cell Carcinoma

Epigenetic Regulator KDM4D Restricts Tumorigenesis via Modulating SYVN1/HMGB1 Ubiquitination Axis in Esophageal Squamous Cell Carcinoma

Active endogenous retroviral elements in human pluripotent stem cells play a role in regulating host gene expression

It’s Getting Complicated—A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy

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