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Transcriptional Control of Metabolism in Cancers

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 14476

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Special Issue Editor

Dr. Catherine Teyssier

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Guest Editor

Institute of Research in Cancerology of Montpellier, University of Montpellier, 34298 Montpellier, France
Interests: transcription; nuclear receptors; coregulators; cancer; metabolism; glycolysis

Special Issue Information

Dear Colleagues,

Transcription factors are functional proteins that regulate the expression of their target genes in response to specific signals. Signaling pathways resulting in post-transcriptional modifications, protein-protein interactions, and ligand binding can turn on transcription factors. Once activated, they can recruit multi-protein complexes that modify chromatin resulting in the transcription of target genes. Through the regulation of their target genes, transcription factors control most of the cellular pathways, such as proliferation and differentiation, but also metabolism. Recently, dysfunctions in gene expression and metabolism have appeared closely linked, contributing to make metabolism a key feature of cancers and potentially a target for anti-cancer treatments. In this Special Issue, we are pleased to invite original manuscripts focusing on the role of transcription factors in cancer metabolism at the molecular level.

Dr. Catherine Teyssier
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

transcription factors
cancer
metabolism
reprogramming
glucose
lipids
amino-acids
gene expression

Published Papers (7 papers)

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Research

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11 pages, 1218 KiB

Open AccessArticle

Immuno-Stimulating Activity of 1,25-Dihydroxyvitamin D in Blood Cells from Five Healthy People and in Blasts from Five Patients with Leukemias and Pre-Leukemic States

by Aleksandra Marchwicka, Kuba Nowak, Anastasiia Satyr, Dariusz Wołowiec and Ewa Marcinkowska

Int. J. Mol. Sci. 2023, 24(7), 6504; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076504 - 30 Mar 2023

Cited by 1 | Viewed by 1295

Abstract

(1) Hematological malignancies are characterized by an immortalization, uncontrolled proliferation of blood cells and their differentiation block, followed by the loss of function. The primary goal in the treatment of leukemias is the elimination of rapidly proliferating leukemic cells (named blasts). However, chemotherapy, which removes proliferating blasts, also prevents the remaining immune cells from being activated. Acute leukemias affect elderly people, who are often not fit to survive aggressive chemotherapy. Therefore, there is a need of milder treatment, named differentiation therapy, which might simulate the immune system of the patient. 1,25-Dihydroxyvitamin D, or low-calcemic analogs of this compound, were proposed as supporting therapy in acute leukemias. (2) Bone marrow blasts from patients with hematological malignancies, and leukocytes from healthy volunteers were ex vivo exposed to 1,25-dihydroxyvitamin D, and then their genomes and transcriptomes were investigated. (3) Our analysis indicates that 1,25-dihydroxyvitamin D regulates in blood cells predominantly genes involved in immune response, such as CAMP (cathelicidin antimicrobial peptide), CP (ceruloplasmin), CXCL9 (C-X-C motif chemokine ligand 9), CD14 (CD14 molecule) or VMO1 (vitelline membrane outer layer 1 homolog). This concerns blood cells from healthy people, as well as blasts from patients with hematological malignancies. In addition, in one patient, 1,25-dihydroxyvitamin D significantly downregulated transcription of genes responsible for cell division and immortalization. (4) In conclusion, the data presented in this paper suggest that addition of 1,25-dihydroxyvitamin D to the currently available treatments would stimulate immune system, inhibit proliferation and reduce immortal potential of blasts. Full article

(This article belongs to the Special Issue Transcriptional Control of Metabolism in Cancers)

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16 pages, 2440 KiB

Open AccessArticle

PRMT1, a Key Modulator of Unliganded Progesterone Receptor Signaling in Breast Cancer

by Lucie Malbeteau, Julien Jacquemetton, Cécile Languilaire, Laura Corbo, Muriel Le Romancer and Coralie Poulard

Int. J. Mol. Sci. 2022, 23(17), 9509; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179509 - 23 Aug 2022

Cited by 2 | Viewed by 1748

Abstract

The progesterone receptor (PR) is a key player in major physiological and pathological responses in women, and the signaling pathways triggered following hormone binding have been extensively studied, particularly with respect to breast cancer development and progression. Interestingly, growing evidence suggests a fundamental role for PR on breast cancer cell homeostasis in hormone-depleted conditions, with hormone-free or unliganded PR (uPR) involved in the silencing of relevant genes prior to hormonal stimulation. We herein identify the protein arginine methyltransferase PRMT1 as a novel actor in uPR signaling. In unstimulated T47D breast cancer cells, PRMT1 interacts and functions alongside uPR and its partners to target endogenous progesterone-responsive promoters. PRMT1 helps to finely tune the silencing of responsive genes, likely by promoting a proper BRCA1-mediated degradation and turnover of unliganded PR. As such, PRMT1 emerges as a key transcriptional coregulator of PR for a subset of relevant progestin-dependent genes before hormonal treatment. Since women experience periods of hormonal fluctuation throughout their lifetime, understanding how steroid receptor pathways in breast cancer cells are regulated when hormones decline may help to determine how to override treatment failure to hormonal therapy and improve patient outcome. Full article

(This article belongs to the Special Issue Transcriptional Control of Metabolism in Cancers)

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18 pages, 3516 KiB

Open AccessArticle

Multi-Level Control of the ATM/ATR-CHK1 Axis by the Transcription Factor E4F1 in Triple-Negative Breast Cancer

by Kalil Batnini, Thibault Houles, Olivier Kirsh, Stanislas Du Manoir, Mehdi Zaroual, Hélène Delpech, Chloé Fallet, Matthieu Lacroix, Laurent Le Cam, Charles Theillet, Claude Sardet and Geneviève Rodier

Int. J. Mol. Sci. 2022, 23(16), 9217; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169217 - 16 Aug 2022

Cited by 2 | Viewed by 2096

Abstract

E4F1 is essential for early embryonic mouse development and for controlling the balance between proliferation and survival of actively dividing cells. We previously reported that E4F1 is essential for the survival of murine p53-deficient cancer cells by controlling the expression of genes involved in mitochondria functions and metabolism, and in cell-cycle checkpoints, including CHEK1, a major component of the DNA damage and replication stress responses. Here, combining ChIP-Seq and RNA-Seq approaches, we identified the transcriptional program directly controlled by E4F1 in Human Triple-Negative Breast Cancer cells (TNBC). E4F1 binds and regulates a limited list of direct target genes (57 genes) in these cells, including the human CHEK1 gene and, surprisingly, also two other genes encoding post-transcriptional regulators of the ATM/ATR-CHK1 axis, namely, the TTT complex component TTI2 and the phosphatase PPP5C, that are essential for the folding and stability, and the signaling of ATM/ATR kinases, respectively. Importantly, E4F1 also binds the promoter of these genes in vivo in Primary Derived Xenograft (PDX) of human TNBC. Consequently, the protein levels and signaling of CHK1 but also of ATM/ATR kinases are strongly downregulated in E4F1-depleted TNBC cells resulting in a deficiency of the DNA damage and replicative stress response in these cells. The E4F1-depleted cells fail to arrest into S-phase upon treatment with the replication-stalling agent Gemcitabine, and are highly sensitized to this drug, as well as to other DNA-damaging agents, such as Cisplatin. Altogether, our data indicate that in breast cancer cells the ATM/ATR-CHK1 signaling pathway and DNA damage-stress response are tightly controlled at the transcriptional and post-transcriptional level by E4F1. Full article

(This article belongs to the Special Issue Transcriptional Control of Metabolism in Cancers)

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12 pages, 1931 KiB

Open AccessArticle

The Transcription Coregulator RIP140 Inhibits Cancer Cell Proliferation by Targeting the Pentose Phosphate Pathway

by Valentin Jacquier, Delphine Gitenay, Vincent Cavaillès and Catherine Teyssier

Int. J. Mol. Sci. 2022, 23(13), 7419; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137419 - 04 Jul 2022

Cited by 3 | Viewed by 1829

Abstract

Cancer cells switch their metabolism toward glucose metabolism to sustain their uncontrolled proliferation. Consequently, glycolytic intermediates are diverted into the pentose phosphate pathway (PPP) to produce macromolecules necessary for cell growth. The transcription regulator RIP140 controls glucose metabolism in tumor cells, but its role in cancer-associated reprogramming of cell metabolism remains poorly understood. Here, we show that, in human breast cancer cells and mouse embryonic fibroblasts, RIP140 inhibits the expression of the gene-encoding G6PD, the first enzyme of the PPP. RIP140 deficiency increases G6PD activity as well as the level of NADPH, a reducing cofactor essential for macromolecule synthesis. Moreover, G6PD knock-down inhibits the gain of proliferation observed when RIP140 expression is reduced. Importantly, RIP140-deficient cells are more sensitive to G6PD inhibition in cell proliferation assays and tumor growth experiments. Altogether, this study describes a novel role for RIP140 in regulating G6PD levels, which links its effect on breast cancer cell proliferation to metabolic rewiring. Full article

(This article belongs to the Special Issue Transcriptional Control of Metabolism in Cancers)

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Review

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17 pages, 1928 KiB

Open AccessReview

Multifaceted Transcriptional Network of Estrogen-Related Receptor Alpha in Health and Disease

by Catherine Cerutti, Jing-Ru Shi and Jean-Marc Vanacker

Int. J. Mol. Sci. 2023, 24(5), 4265; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054265 - 21 Feb 2023

Cited by 4 | Viewed by 1755

Abstract

Estrogen-related receptors (ERRα, β and γ in mammals) are orphan members of the nuclear receptor superfamily acting as transcription factors. ERRs are expressed in several cell types and they display various functions in normal and pathological contexts. Amongst others, they are notably involved in bone homeostasis, energy metabolism and cancer progression. In contrast to other nuclear receptors, the activities of the ERRs are apparently not controlled by a natural ligand but they rely on other means such as the availability of transcriptional co-regulators. Here we focus on ERRα and review the variety of co-regulators that have been identified by various means for this receptor and their reported target genes. ERRα cooperates with distinct co-regulators to control the expression of distinct sets of target genes. This exemplifies the combinatorial specificity of transcriptional regulation that induces discrete cellular phenotypes depending on the selected coregulator. We finally propose an integrated view of the ERRα transcriptional network. Full article

(This article belongs to the Special Issue Transcriptional Control of Metabolism in Cancers)

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21 pages, 3867 KiB

Open AccessReview

CircAMOTL1 RNA and AMOTL1 Protein: Complex Functions of AMOTL1 Gene Products

by Joanna Sadlak, Ila Joshi, Tomasz J. Prószyński and Anthony Kischel

Int. J. Mol. Sci. 2023, 24(3), 2103; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032103 - 20 Jan 2023

Cited by 2 | Viewed by 1651

Abstract

The complexity of the cellular proteome facilitates the control of a wide range of cellular processes. Non-coding RNAs, including microRNAs and long non-coding RNAs, greatly contribute to the repertoire of tools used by cells to orchestrate various functions. Circular RNAs (circRNAs) constitute a specific class of non-coding RNAs that have recently emerged as a widely generated class of molecules produced from many eukaryotic genes that play essential roles in regulating cellular processes in health and disease. This review summarizes current knowledge about circRNAs and focuses on the functions of AMOTL1 circRNAs and AMOTL1 protein. Both products from the AMOTL1 gene have well-known functions in physiology, cancer, and other disorders. Using AMOTL1 as an example, we illustrate how focusing on both circRNAs and proteins produced from the same gene contributes to a better understanding of gene functions. Full article

(This article belongs to the Special Issue Transcriptional Control of Metabolism in Cancers)

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20 pages, 5013 KiB

Open AccessReview

SP and KLF Transcription Factors in Cancer Metabolism

by Emilia J. Orzechowska-Licari, Joseph F. LaComb, Aisharja Mojumdar and Agnieszka B. Bialkowska

Int. J. Mol. Sci. 2022, 23(17), 9956; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179956 - 01 Sep 2022

Cited by 12 | Viewed by 3103

Abstract

Tumor development and progression depend on reprogramming of signaling pathways that regulate cell metabolism. Alterations to various metabolic pathways such as glycolysis, oxidative phosphorylation, lipid metabolism, and hexosamine biosynthesis pathway are crucial to sustain increased redox, bioenergetic, and biosynthesis demands of a tumor cell. Transcription factors (oncogenes and tumor suppressors) play crucial roles in modulating these alterations, and their functions are tethered to major metabolic pathways under homeostatic conditions and disease initiation and advancement. Specificity proteins (SPs) and Krüppel-like factors (KLFs) are closely related transcription factors characterized by three highly conserved zinc fingers domains that interact with DNA. Studies have demonstrated that SP and KLF transcription factors are expressed in various tissues and regulate diverse processes such as proliferation, differentiation, apoptosis, inflammation, and tumorigenesis. This review highlights the role of SP and KLF transcription factors in the metabolism of various cancers and their impact on tumorigenesis. A better understanding of the role and underlying mechanisms governing the metabolic changes during tumorigenesis could provide new therapeutic opportunities for cancer treatment. Full article

(This article belongs to the Special Issue Transcriptional Control of Metabolism in Cancers)

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