Tristetraprolin-mediated hexokinase 2 expression regulation contributes to glycolysis in cancer cells

Kim, Dong Jun; Vo, Mai-Tram; Choi, Seong Hee; Lee, Ji-Heon; Jeong, Sang Hoon; Hong, Chung Hwan; Kim, Jong Soo; Lee, Unn Hwa; Chung, Hyung-Min; Lee, Byung Ju; Cho, Wha Ja; Park, Jeong Woo

doi:10.1091/mbc.e18-09-0606

Cited by 17 publications

(16 citation statements)

References 49 publications

(67 reference statements)

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“…Tristetraprolin (TTP), is a well-known ARE-binding protein able to promote the degradation of ARE-containing transcripts ( Carballo et al, 1998 ; Chen et al, 2001 ; Lykke-Andersen and Wagner, 2005 ). In mammals, TTP is critical for the downregulation of HXKII expression in cancer cells as it enhances the degradation of the HXKII transcript, thus, suppressing the glycolytic capacity of cancer cells and reducing both the extracellular acidification rate and the oxygen consumption rate of cancer cells ( Kim et al, 2019 ).…”

Section: Regulation Mechanisms Of Hexokinases’ Moonlighting Functionsmentioning

confidence: 99%

Moonlighting Proteins: The Case of the Hexokinases

Rodríguez-Saavedra

Morgado-Martínez

Burgos-Palacios

et al. 2021

Front. Mol. Biosci.

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Moonlighting proteins are defined as proteins with two or more functions that are unrelated and independent to each other, so that inactivation of one of them should not affect the second one and vice versa. Intriguingly, all the glycolytic enzymes are described as moonlighting proteins in some organisms. Hexokinase (HXK) is a critical enzyme in the glycolytic pathway and displays a wide range of functions in different organisms such as fungi, parasites, mammals, and plants. This review discusses HXKs moonlighting functions in depth since they have a profound impact on the responses to nutritional, environmental, and disease challenges. HXKs’ activities can be as diverse as performing metabolic activities, as a gene repressor complexing with other proteins, as protein kinase, as immune receptor and regulating processes like autophagy, programmed cell death or immune system responses. However, most of those functions are particular for some organisms while the most common moonlighting HXK function in several kingdoms is being a glucose sensor. In this review, we also analyze how different regulation mechanisms cause HXK to change its subcellular localization, oligomeric or conformational state, the response to substrate and product concentration, and its interactions with membrane, proteins, or RNA, all of which might impact the HXK moonlighting functions.

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Section: Regulation Mechanisms Of Hexokinases’ Moonlighting Functionsmentioning

confidence: 99%

Moonlighting Proteins: The Case of the Hexokinases

Rodríguez-Saavedra

Morgado-Martínez

Burgos-Palacios

et al. 2021

Front. Mol. Biosci.

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“…The 3′UTR is important for the post-transcriptional regulation of genes. Many RBPs, including human antigen R (HuR) [30], tristetraprolin (TTP) [31], and MCPIP1, have been reported to regulate mRNA stability by the 3'UTR.…”

Section: Discussionmentioning

confidence: 99%

Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

Lü

Wang

et al. 2020

Preprint

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Background: Dysregulation of cell cycle progression is one of the common features of human cancer cells, however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest induction in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant association with patient survival. Quantitative real-time PCR and western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse free survival of patients with breast cancer. Roquin1 overexpression inhibited breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through targeting the stem–loop structure in the 3’untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.Conclusions: Our findings demonstrated that Roquin1 was a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might as a potential molecular target for breast cancer treatment.

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“…The 3¢UTR is important for the post-transcriptional regulation of genes. Many RBPs, including human antigen R (HuR) [32], tristetraprolin (TTP) [33], and MCPIP1, have been reported to regulate mRNA stability by the 3'UTR. Indeed, Roquin1 inhibits luciferase activity through the 3'UTRs of cell cycle-promoting genes.…”

Section: Discussionmentioning

confidence: 99%

Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes

Zhou

Wang

et al. 2020

Preprint

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Background: Dysregulation of cell cycle progression is a common feature of human cancer cells; however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and its association with patient survival. Quantitative real-time PCR and Western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assays, flow cytometry, and in vivo analyses were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA sequencing was applied to identify the differentially expressed genes regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse-free survival of patients with breast cancer. Roquin1 overexpression inhibited cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizes cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2), by targeting the stem–loop structure in the 3' untranslated region (3'UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.Conclusions: Our findings demonstrated that Roquin1 is a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might be a potential molecular target for breast cancer treatment.

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Tristetraprolin-mediated hexokinase 2 expression regulation contributes to glycolysis in cancer cells

Cited by 17 publications

References 49 publications

Moonlighting Proteins: The Case of the Hexokinases

Moonlighting Proteins: The Case of the Hexokinases

Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

Roquin1 inhibits the proliferation of breast cancer cells by inducing G1/S cell cycle arrest via selectively destabilizing the mRNAs of cell cycle–promoting genes

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