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Ruiz‐Rodado, Victor; Dowdy, Tyrone; Lita, Adrian; Kramp, Tamalee; Zhang, Meili; Jung, Jinkyu; Dios‐Esponera, Ana; Zhang, Lumin; Herold‐Mende, Christel C.; Camphausen, Kevin; Gilbert, Mark R.; Larion, Mioara
doi: 10.1002/1878-0261.13148pmid: 34856072
Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that make cancer cells require certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C‐tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support glutathione synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine‐deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine‐free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, even though higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine‐related metabolite levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.
Jung, Minsun; Lee, Kyung‐Min; Im, Yebin; Seok, Seung Hyeok; Chung, Hyewon; Kim, Da Young; Han, Dohyun; Lee, Cheng Hyun; Hwang, Eun Hye; Park, Soo Young; Koh, Jiwon; Kim, Bohyun; Nikas, Ilias P.; Lee, Hyebin; Hwang, Daehee; Ryu, Han Suk
Wang, Qiong; Karvelsson, Sigurdur Trausti; Johannsson, Freyr; Vilhjalmsson, Arnar Ingi; Hagen, Lars; Miranda Fonseca, Davi; Sharma, Animesh; Slupphaug, Geir; Rolfsson, Ottar
doi: 10.1002/1878-0261.13172pmid: 34942055
Metabolic rewiring is one of the indispensable drivers of epithelial–mesenchymal transition (EMT) involved in breast cancer metastasis. In this study, we explored the metabolic changes during spontaneous EMT in three separately established breast EMT cell models using a proteomic approach supported by metabolomic analysis. We identified common proteomic changes, including the expression of CDH1, CDH2, VIM, LGALS1, SERPINE1, PKP3, ATP2A2, JUP, MTCH2, RPL26L1 and PLOD2. Consistently altered metabolic enzymes included the following: FDFT1, SORD, TSTA3 and UDP‐glucose dehydrogenase (UGDH). Of these, UGDH was most prominently altered and has previously been associated with breast cancer patient survival. siRNA‐mediated knock‐down of UGDH resulted in delayed cell proliferation and dampened invasive potential of mesenchymal cells and downregulated expression of the EMT transcription factor SNAI1. Metabolomic analysis revealed that siRNA‐mediated knock‐down of UGDH decreased intracellular glycerophosphocholine (GPC), whereas levels of acetylaspartate (NAA) increased. Finally, our data suggested that platelet‐derived growth factor receptor beta (PDGFRB) signalling was activated in mesenchymal cells. siRNA‐mediated knock‐down of PDGFRB downregulated UGDH expression, potentially via NFkB‐p65. Our results support an unexplored relationship between UGDH and GPC, both of which have previously been independently associated with breast cancer progression.
Guimarães‐Teixeira, Catarina; Lobo, João; Miranda‐Gonçalves, Vera; Barros‐Silva, Daniela; Martins‐Lima, Cláudia; Monteiro‐Reis, Sara; Sequeira, José Pedro; Carneiro, Isa; Correia, Margareta P.; Henrique, Rui; Jerónimo, Carmen
doi: 10.1002/1878-0261.13181pmid: 35048498
N6‐methyladenosine (m6A) and its regulatory proteins have been associated with tumorigenesis in several cancer types. However, knowledge on the mechanistic network related to m6A in bladder cancer (BlCa) is rather limited, requiring further investigation of its functional role. We aimed to uncover the biological role of m6A and related proteins in BlCa and understand how this influences tumor aggressiveness. N6‐adenosine‐methyltransferase catalytic subunit (METTL3), N6‐adenosine‐methyltransferase noncatalytic subunit (METTL14), protein virilizer homolog (VIRMA), and RNA demethylase ALKBH5 (ALKBH5) had significantly lower expression levels in BlCa compared to that in normal urothelium. METTL14 knockdown led to disruption of the remaining methyltransferase complex and a decrease in m6A abundance, as well as overall reduced tumor aggressiveness (decreased cell invasion and migration capacity and increased apoptosis). Furthermore, in vivo, METTL14 knockdown caused tumor size reduction. Collectively, we propose methyltransferase METTL14 as a key component for m6A RNA deposit and that it is closely related to BlCa progression, playing an important role in tumor aggressiveness. These data contribute to a better understanding of the m6A writer complex, which might constitute an appealing therapeutic target.
Park, Jee Won; Kim, Yesol; Lee, Soo‐been; Oh, Chae Won; Lee, Eun Ji; Ko, Je Yeong; Park, Jong Hoon
doi: 10.1002/1878-0261.13180pmid: 35029026
Autophagy has a dual role in the maintenance of cancer stem cells (CSCs), but the precise relationship between autophagy and cancer stemness requires further investigation. In this study, it was found that luminal and triple‐negative breast cancers require distinct therapeutic approaches because of their different amounts of autophagy flux. We identified that autophagy flux was inhibited in triple‐negative breast cancer (TNBC) CSCs. Moreover, miRNA‐181a (miR‐181a) expression is upregulated in both TNBC CSCs and patient tissues. Autophagy‐related 5 (ATG5) and autophagy‐related 2B (ATG2B) participate in the early formation of autophagosomes and were revealed as targets of miR‐181a. Inhibition of miR‐181a expression led to attenuation of TNBC stemness and an increase in autophagy flux. Furthermore, treatment with curcumin led to attenuation of cancer stemness in TNBC CSCs; the expression of ATG5 and ATG2B was enhanced and there was an increase of autophagy flux. These results indicated that ATG5 and ATG2B are involved in the suppression of cancer stemness in TNBC. In summary, autophagy inhibits cancer stemness through the miR‐181a‐regulated mechanism in TNBC. Promoting tumor‐suppressive autophagy using curcumin may be a potential method for the treatment of TNBC.
Galán‐Martínez, Javier; Stamatakis, Konstantinos; Sánchez‐Gómez, Inés; Vázquez‐Cuesta, Silvia; Gironés, Núria; Fresno, Manuel
doi: 10.1002/1878-0261.13085pmid: 34623757
Colorectal cancer (CRC) is a very common life‐threatening malignancy. Transcription factor‐like 5 (TCFL5) has been suggested to be involved in CRC. Here, we describe the expression of four alternative transcripts of TCFL5 and their relevance in CRC. Complete deletion of all isoforms drastically decreased pro‐tumoural properties such as spheroids formation and in vivo tumour growth, although increased migration in CRC cell lines. Overexpression of the two main isoforms, TCFL5_E8 and CHA, had opposite effects: TCFL5_E8 reduced proliferation and spheroids formation, while CHA increased them. TCFL5_E8 reduced in vivo tumour formation, while CHA had no effect. In addition, TCFL5_E8 and CHA have different roles in the regulation of the pluripotency‐related genes SOX2 and KLF4. Both isoforms bind directly to their promoters; however, TCFL5_E8 induced SOX2 and reduced KLF4 mRNA levels, whereas CHA did the opposite. Together, our results show that TCFL5 plays an important role in the development of CRC, being however isoform‐specific. This work also points to the need to analyse separately TCFL5 isoforms in cancer, due to their different and opposite functions.
García‐Gómez, Pedro; Golán, Irene; S. Dadras, Mahsa; Mezheyeuski, Artur; Bellomo, Claudia; Tzavlaki, Kalliopi; Morén, Anita; Carreras‐Puigvert, Jordi; Caja, Laia
doi: 10.1002/1878-0261.13200pmid: 35203105
Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass is characterised by a small cellular subpopulation – glioblastoma stem cells (GSCs) – that has been held responsible for glioblastoma initiation, cell invasion, proliferation, relapse and resistance to chemo‐ and radiotherapy. Targeted therapies against GSCs are crucial, as is understanding the molecular mechanisms that govern the GSCs. Transforming growth factor β (TGFβ) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGFβ in a transcriptomic analysis of two different patient‐derived GSCs, we found NADPH oxidase 4 (NOX4) as one of the top upregulated genes. Interestingly, when patient tissues were analysed, NOX4 expression was found to be higher in GSCs versus differentiated cells. A functional analysis of the role of NOX4 downstream of TGFβ in several patient‐derived GSCs showed that TGFβ does indeed induce NOX4 expression and increases ROS production in a NOX4‐dependent manner. NOX4 downstream of TGFβ regulates GSC proliferation, and NOX4 expression is necessary for TGFβ‐induced expression of stem cell markers and of the transcription factor nuclear factor erythroid 2‐related factor 2 (NRF2), which in turn controls the cell’s antioxidant and metabolic responses. Interestingly, overexpression of NOX4 recapitulates the effects induced by TGFβ in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.
Papaiz, Debora D’Angelo; Rius, Flávia Eichemberger; Ayub, Ana Luísa Pedroso; Origassa, Clarice S.; Gujar, Hemant; Pessoa, Diogo de Oliveira; Reis, Eduardo Moraes; Nsengimana, Jérémie; Newton‐Bishop, Julia; Mason, Christopher E.; Weisenberger, Daniel J.; Liang, Gangning; Jasiulionis, Miriam Galvonas
Chebly, Alain; Ropio, Joana; Peloponese, Jean‐Marie; Poglio, Sandrine; Prochazkova‐Carlotti, Martina; Cherrier, Floriane; Ferrer, Jacky; Idrissi, Yamina; Segal‐Bendirdjian, Evelyne; Chouery, Eliane; Farra, Chantal; Pham‐Ledard, Anne; Beylot‐Barry, Marie; Merlio, Jean‐Philippe; Tomb, Roland; Chevret, Edith
Showing 1 to 10 of 11 Articles
Metabolic dysregulation is an important hallmark of cancer. Nicotinamide (NAM), a water‐soluble amide form of niacin (vitamin B3), is currently available as a supplement for maintaining general physiologic functions. NAM is a crucial regulator of mitochondrial metabolism and redox reactions. In this study, we aimed to identify the mechanistic link between NAM‐induced metabolic regulation and the therapeutic efficacy of NAM in triple‐negative breast cancer (TNBC). The combined analysis using multiomics systems biology showed that NAM decreased mitochondrial membrane potential and ATP production, but increased the activities of reverse electron transport (RET), fatty acid β‐oxidation and glycerophospholipid/sphingolipid metabolic pathways in TNBC, collectively leading to an increase in the levels of reactive oxygen species (ROS). The increased ROS levels triggered apoptosis and suppressed tumour growth and metastasis of TNBC in both human organoids and xenograft mouse models. Our results showed that NAM treatment leads to cancer cell death in TNBC via mitochondrial dysfunction and activation of ROS by bifurcating metabolic pathways (RET and lipid metabolism); this provides insights into the repositioning of NAM supplement as a next‐generation anti‐metabolic agent for TNBC treatment.
In addition to mutations, epigenetic alterations are important contributors to malignant transformation and tumor progression. The aim of this work was to identify epigenetic events in which promoter or gene body DNA methylation induces gene expression changes that drive melanocyte malignant transformation and metastasis. We previously developed a linear mouse model of melanoma progression consisting of spontaneously immortalized melanocytes, premalignant melanocytes, a nonmetastatic tumorigenic, and a metastatic cell line. Here, through the integrative analysis of methylome and transcriptome data, we identified the relationship between promoter and/or gene body DNA methylation alterations and gene expression in early, intermediate, and late stages of melanoma progression. We identified adenylate cyclase type 3 (Adcy3) and inositol polyphosphate 4‐phosphatase type II (Inpp4b), which affect tumor growth and metastatic potential, respectively. Importantly, the gene expression and DNA methylation profiles found in this murine model of melanoma progression were correlated with available clinical data from large population‐based primary melanoma cohorts, revealing potential prognostic markers.
Cutaneous T‐cell lymphomas (CTCLs) are telomerase‐positive tumors expressing hTERT, although neither gene rearrangement/amplification nor promoter hotspot mutations could explain the hTERT re‐expression. As the hTERT promoter is rich in CpG, we investigated the contribution of epigenetic mechanisms in its re‐expression. We analyzed hTERT promoter methylation status in CTCL cells compared with healthy cells. Gene‐specific methylation analyses revealed a common methylation pattern exclusively in tumor cells. This methylation pattern encompassed a hypermethylated distal region from −650 to −150 bp and a hypomethylated proximal region from −150 to +150 bp. Interestingly, the hypermethylated region matches with the recently named TERT hypermethylated oncogenic region (THOR). THOR has been associated with telomerase reactivation in many cancers, but it has so far not been reported in cutaneous lymphomas. Additionally, we assessed the effect of THOR on two histone deacetylase inhibitors (HDACi), romidepsin and vorinostat, both approved for CTCL treatment and a DNA methyltransferase inhibitor (DNMTi) 5‐azacytidine, unapproved for CTCL. Contrary to our expectations, the findings reported herein revealed that THOR methylation is relatively stable under these epigenetic drugs' pressure, whereas these drugs reduced the hTERT gene expression.