Single-Cell Transcriptome Analysis Reveals Estrogen Signaling Coordinately Augments One-Carbon, Polyamine, and Purine Synthesis in Breast Cancer

Zhu, Detu; Zhao, Zhenqun; Cui, Guimei; Chang, Shiehong; Hu, Lingling; See, Yi Xiang; Lim, Michelle Gek Liang; Guo, Dajiang; Chen, Xin; Poudel, Barun; Robson, Paul; Luo, Yan; Cheung, Edwin

doi:10.1016/j.celrep.2018.10.093

Cited by 40 publications

(26 citation statements)

References 36 publications

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“…In a similar manner, tRNA signalling is known to be an intracellular target of oestrogen, and an increased abundance of tRNA has been associated with proliferating cells 51,52 . Indeed, from the single-cell data, we observed the highest fraction of proliferative β cells in the PEG-insulin and GLP-1-oestrogen conjugate cotreated mice ( Fig.…”

Section: Ucn3mentioning

confidence: 95%

Targeted pharmacological therapy restores β-cell function for diabetes remission

et al. 2020

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Dedifferentiation of insulin-secreting β cells in the islets of Langerhans has been proposed to be a major mechanism of β-cell dysfunction. Whether dedifferentiated β cells can be targeted by pharmacological intervention for diabetes remission, and ways in which this could be accomplished, are unknown as yet. Here we report the use of streptozotocin-induced diabetes to study β-cell dedifferentiation in mice. Single-cell RNA sequencing (scRNA-seq) of islets identified markers and pathways associated with β-cell dedifferentiation and dysfunction. Single and combinatorial pharmacology further show that insulin treatment triggers insulin receptor pathway activation in β cells and restores maturation and function for diabetes remission. Additional β-cell selective delivery of oestrogen by Glucagon-like peptide-1 (GLP-1-oestrogen conjugate) decreases daily insulin requirements by 60%, triggers oestrogen-specific activation of the endoplasmic-reticulum-associated protein degradation system, and further increases β-cell survival and regeneration. GLP-1-oestrogen also protects human β cells against cytokineinduced dysfunction. This study not only describes mechanisms of β-cell dedifferentiation and regeneration, but also reveals pharmacological entry points to target dedifferentiated β cells for diabetes remission.There are amendments to this paper NATURE METABoLiSM | VOL 2 | FEBRUARy 2020 | 192-209 | www.nature.com/natmetab 192 Articles NATuRE METAboLiSM autoimmunity in the mSTZ model permits the investigation of the fate of those remaining β cells and the effect of pharmacological treatment on β-cell protection and regeneration.

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Section: Ucn3mentioning

confidence: 95%

Targeted pharmacological therapy restores β-cell function for diabetes remission

et al. 2020

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“…PGC1α/ERRα directly represses several SGOCP enzymes downstream of the metformin-dependent activation of AMPK, which underlies the sensitivity of ERRα-positive (ER + ) breast cancer to the DHFR antagonist methotrexate (Audet-Walsh et al, 2016). Conversely, estrogens promote an ERα-dependent increase in polyamine and purine synthesis via metabolic reprogramming of the mitochondrial branch of the SGOCP (Zhu et al, 2018). Also in ER + breast cancer, targeting of ESRP1 down-regulates the lipogenic program and PHGDH expression and stops growth of endocrine-resistant breast cancer cells (Gökmen-Polar et al, 2019;Fig.…”

Section: The Sgocp Regulationmentioning

confidence: 99%

The complexity of the serine glycine one-carbon pathway in cancer

Reina-Campos

Diaz-Meco

Moscat

2019

Journal of Cell Biology

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The serine glycine and one-carbon pathway (SGOCP) is a crucially important metabolic network for tumorigenesis, of unanticipated complexity, and with implications in the clinic. Solving how this network is regulated is key to understanding the underlying mechanisms of tumor heterogeneity and therapy resistance. Here, we review its role in cancer by focusing on key enzymes with tumor-promoting functions and important products of the SGOCP that are of physiological relevance for tumorigenesis. We discuss the regulatory mechanisms that coordinate the metabolic flux through the SGOCP and their deregulation, as well as how the actions of this metabolic network affect other cells in the tumor microenvironment, including endothelial and immune cells.

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“…In spite of the high inter-patient heterogeneity, we identified that 4 stem cell quiescence-associated genes, ALDH1L1, HOPX, WNT5A and SOX9, were convergently hypomethylated in all the post-NAC samples. ALDH1L1 is a key enzyme that negatively regulate the one-carbon metabolism to limit cell proliferation [36, 37] and is a marker for quiescent neuron stem cells [23]. WNT5A is a non-canonical Wnt ligand and functions to maintain the quiescent state of multiple adult stem cells, such as hematopoietic stem cells [24] and neural stem cells [25].…”

Section: Discussionmentioning

confidence: 99%

Regional methylome profiling reveals dynamic epigenetic heterogeneity and convergent hypomethylation of stem cell quiescence-associated genes in breast cancer following neoadjuvant chemotherapy

et al. 2019

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BackgroundNeoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~ 30% of patients with breast cancer. However, aberrant DNA methylation alterations are frequent events during breast cancer progression and acquisition of chemoresistance. We aimed to characterize the inter- and intra-tumor methylation heterogeneity (MH) in breast cancer following NAC.MethodsDNA methylation profiles of spatially separated regions of breast tumors before and after NAC treatment were investigated using high-density methylation microarray. Methylation levels of genes of interest were further examined using multiplexed MethyLight droplet digital PCR (ddPCR).ResultsWe have discovered different levels of intra-tumor MH in breast cancer patients. Moreover, NAC dramatically altered the methylation profiles and such changes were highly heterogeneous between the patients. Despite the high inter-patient heterogeneity, we identified that stem cell quiescence-associated genes ALDH1L1, HOPX, WNT5A and SOX9 were convergently hypomethylated across all the samples after NAC treatment. Furthermore, by using MethyLight ddPCR, we verified that the methylation levels of these 4 genes were significantly lower in breast tumor samples after NAC than those before NAC.ConclusionsOur study has revealed that NAC dramatically alters epigenetic heterogeneity in breast cancer and induces convergent hypomethylation of stem cell quiescence-associated genes, ALDH1L1, HOPX, WNT5A and SOX9, which can potentially be developed as therapeutic targets or biomarkers for chemoresistance.Electronic supplementary materialThe online version of this article (10.1186/s13578-019-0278-y) contains supplementary material, which is available to authorized users.

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Single-Cell Transcriptome Analysis Reveals Estrogen Signaling Coordinately Augments One-Carbon, Polyamine, and Purine Synthesis in Breast Cancer

Cited by 40 publications

References 36 publications

Targeted pharmacological therapy restores β-cell function for diabetes remission

Targeted pharmacological therapy restores β-cell function for diabetes remission

The complexity of the serine glycine one-carbon pathway in cancer

Regional methylome profiling reveals dynamic epigenetic heterogeneity and convergent hypomethylation of stem cell quiescence-associated genes in breast cancer following neoadjuvant chemotherapy

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