bims-cadres 2022-11-27 papers

bims-cadres

Biomed News

on Cancer drug resistance

Issue of 2022‒11‒27
nine papers selected by
Rana Gbyli
Yale University

Stearate-derived very long-chain fatty acids are indispensable to tumor growth.
BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy.
circPRKAA1 activates a Ku80/Ku70/SREBP-1 axis driving de novo fatty acid synthesis in cancer cells.
Acetyl-CoA regulates lipid metabolism and histone acetylation modification in cancer.
JAK-STAT signaling in inflammatory breast cancer enables chemotherapy-resistant cell states.
COX7A1 enhances the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via regulating mitochondrial metabolism.
Mitochondrial genomic integrity and the nuclear epigenome in health and disease.
Histone acetyltransferase 1 (HAT1) acetylates hypoxia-inducible factor 2 alpha (HIF2A) to execute hypoxia response.
Acetyl-CoA carboxylase 1 depletion suppresses de novo fatty acid synthesis and mitochondrial β-oxidation in castration-resistant prostate cancer cells.

EMBO J. 2022 Nov 21. e111268

Stearate-derived very long-chain fatty acids are indispensable to tumor growth.

Qiaoyun Chu, Ping Liu, Yihan Song, Ronghui Yang, Jing An, Xuewei Zhai, Jing Niu, Chuanzhen Yang, Binghui Li.

  Reprogramming of lipid metabolism is emerging as a hallmark of cancer, yet involvement of specific fatty acids (FA) species and related enzymes in tumorigenesis remains unclear. While previous studies have focused on involvement of long-chain fatty acids (LCFAs) including palmitate in cancer, little attention has been paid to the role of very long-chain fatty acids (VLCFAs). Here, we show that depletion of acetyl-CoA carboxylase (ACC1), a critical enzyme involved in the biosynthesis of fatty acids, inhibits both de novo synthesis and elongation of VLCFAs in human cancer cells. ACC1 depletion markedly reduces cellular VLCFA but only marginally influences LCFA levels, including palmitate that can be nutritionally available. Therefore, tumor growth is specifically susceptible to regulation of VLCFAs. We further demonstrate that VLCFA deficiency results in a significant decrease in ceramides as well as downstream glucosylceramides and sphingomyelins, which impairs mitochondrial morphology and renders cancer cells sensitive to oxidative stress and cell death. Taken together, our study highlights that VLCFAs are selectively required for cancer cell survival and reveals a potential strategy to suppress tumor growth.

Keywords:  acetyl-CoA carboxylase; fatty acid elongation; fatty acid synthase; mitochondria potential; very long-chain fatty acids

DOI:  https://doi.org/10.15252/embj.2022111268
Nat Commun. 2022 Nov 19. 13(1): 7113

BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy.

Kimberley McGrail, Paula Granado-Martínez, Rosaura Esteve-Puig, Sara García-Ortega, Yuxin Ding, Sara Sánchez-Redondo, Berta Ferrer, Javier Hernandez-Losa, Francesc Canals, Anna Manzano, Aura Navarro-Sabaté, Ramón Bartrons, Oscar Yanes, Mileidys Pérez-Alea, Eva Muñoz-Couselo, Vicenç Garcia-Patos, Juan A Recio.

NRAS-mutated melanoma lacks a specific line of treatment. Metabolic reprogramming is considered a novel target to control cancer; however, NRAS-oncogene contribution to this cancer hallmark is mostly unknown. Here, we show that NRASQ61-mutated melanomas specific metabolic settings mediate cell sensitivity to sorafenib upon metabolic stress. Mechanistically, these cells are dependent on glucose metabolism, in which glucose deprivation promotes a switch from CRAF to BRAF signaling. This scenario contributes to cell survival and sustains glucose metabolism through BRAF-mediated phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2/3 (PFKFB2/PFKFB3). In turn, this favors the allosteric activation of phosphofructokinase-1 (PFK1), generating a feedback loop that couples glycolytic flux and the RAS signaling pathway. An in vivo treatment of NRASQ61 mutant melanomas, including patient-derived xenografts, with 2-deoxy-D-glucose (2-DG) and sorafenib effectively inhibits tumor growth. Thus, we provide evidence for NRAS-oncogene contributions to metabolic rewiring and a proof-of-principle for the treatment of NRASQ61-mutated melanoma combining metabolic stress (glycolysis inhibitors) and previously approved drugs, such as sorafenib.

DOI: https://doi.org/10.1038/s41467-022-34907-0
Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01581-9. [Epub ahead of print]41(8): 111707

circPRKAA1 activates a Ku80/Ku70/SREBP-1 axis driving de novo fatty acid synthesis in cancer cells.

Qidong Li, Hanhui Yao, Yichun Wang, Yang Wu, Rick F Thorne, Youming Zhu, Mian Wu, Lianxin Liu.

  Many metabolism-related genes undergo alternative splicing to generate circular RNAs, but their functions remain poorly understood. Here we report that circPRKAA1, a circular RNA (circRNA) derived from the α1 subunit of AMP-activated protein kinase (AMPK), fulfills a fundamental role in maintaining lipid homeostasis. circPRKAA1 expression facilitates fatty acid synthesis and promotes lipid storage through two coordinated functions. First, circPRKAA1 promotes a tetrameric complex between the Ku80/Ku70 heterodimer and the mature form of sterol regulatory element-binding protein 1 (mSREBP-1) to enhance the stability of mSREBP-1. Second, circPRKAA1 selectively binds to the promoters of the ACC1, ACLY, SCD1, and FASN genes to recruit mSREBP-1, upregulating their transcription and increasing fatty acid synthesis to promote cancer growth. circPRKAA1 biogenesis is negatively regulated by AMPK activity, with lower AMPK activation in hepatocellular carcinoma tissue frequently associated with elevated circPRKAA1 expression. This work identifies circPRKAA1 as an integral element of AMPK-regulated reprogramming of lipid metabolism in cancer cells.

Keywords:  AMPK; CP: Cancer; CP: Metabolism; Ku80/Ku70; SREBP-1; SRSF1; circPRKAA1; fatty acid synthesis

DOI:  https://doi.org/10.1016/j.celrep.2022.111707
Biochim Biophys Acta Rev Cancer. 2022 Nov 17. pii: S0304-419X(22)00162-7. [Epub ahead of print]1878(1): 188837

Acetyl-CoA regulates lipid metabolism and histone acetylation modification in cancer.

Weijing He, Qingguo Li, Xinxiang Li.

  Acetyl-CoA, as an important molecule, not only participates in multiple intracellular metabolic reactions, but also affects the post-translational modification of proteins, playing a key role in the metabolic activity and epigenetic inheritance of cells. Cancer cells require extensive lipid metabolism to fuel for their growth, while also require histone acetylation modifications to increase the expression of cancer-promoting genes. As a raw material for de novo lipid synthesis and histone acetylation, acetyl-CoA has a major impact on lipid metabolism and histone acetylation in cancer. More importantly, in cancer, acetyl-CoA connects lipid metabolism with histone acetylation, forming a more complex regulatory mechanism that influences cancer growth, proliferation, metastasis.

Keywords:  Acetyl-coenzyme A (acetyl-CoA); Cancer; Histone acetylation; Lipid metabolism

DOI:  https://doi.org/10.1016/j.bbcan.2022.188837
Cancer Res. 2022 Nov 21. pii: CAN-22-0423. [Epub ahead of print]

JAK-STAT signaling in inflammatory breast cancer enables chemotherapy-resistant cell states.

Laura E Stevens, Guillermo Peluffo, Xintao Qiu, Daniel Temko, Anne Fassl, Zheqi Li, Anne Trinh, Marco Seehawer, Bojana Jovanovic, Masa Aleckovic, Callahan M Wilde, Renee C Geck, Shaokun Shu, Natalie L Kingston, Nicholas W Harper, Vanessa Almendro, Alanna L Pyke, Shawn B Egri, Malvina Papanastasiou, Kendell Clement, Ningxuan Zhou, Sarah Walker, Jacqueline Salas, So Yeon Park, David A Frank, Alexander Meissner, Jacob D Jaffe, Piotr Sicinski, Alex Toker, Franziska Michor, Henry W Long, Beth A Overmoyer, Kornelia Polyak.

Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy resistant derivatives. Integrated pSTAT3 ChIP-seq and RNA-seq analyses showed pSTAT3 regulates genes related to inflammation and epithelial to mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare pre-existing subpopulations or an acquired change. Lastly, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0423
Cell Death Dis. 2022 Nov 23. 13(11): 988

COX7A1 enhances the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via regulating mitochondrial metabolism.

Yetong Feng, Jiayi Xu, Mengjiao Shi, Rongrong Liu, Lei Zhao, Xin Chen, Miaomiao Li, Yaping Zhao, Jiahui Chen, Wenjing Du, Pengfei Liu.

COX7A1, a subunit of cytochrome c oxidase, holds an important position in the super-assembly which integrates into multi-unit heteromeric complexes peripherally in the mitochondrial electron transport chain (ETC). Recently, some studies indicated the significant potential of COX7A1 in cancer metabolism and therapy. However, the underlying metabolic process and therapy mechanism remain unclear. In this study, COX7A1-overexpressed cell line was established via lentivirus transduction. The relationship between COX7A1 and ferroptosis, a novel form of cell death driven by iron-dependent lipid peroxidation, was further analyzed in different human non-small-cell lung carcinoma (NSCLC) cells respectively. Our results showed that COX7A1 increased the sensitivity of NSCLC cells to the ferroptosis induced by cysteine deprivation via enhancing the tricarboxylic acid (TCA) cycle and the activity of complex IV in mitochondrial ETC. Meanwhile, COX7A1 suppressed mitochondrial dynamics as well as mitochondrial biogenesis and mitophagy through blocking autophagic flux. The autophagy activator, rapamycin, relieved the autophagic blockage and further strengthened the sensitivity to cysteine deprivation-induced ferroptosis of NSCLC cells in vitro and in vivo. Taken together, our data indicate the close association of COX7A1 with cysteine deprivation-induced ferroptosis, and provide a novel insight into the therapy mode against human NSCLC.

DOI: https://doi.org/10.1038/s41419-022-05430-3
Front Endocrinol (Lausanne). 2022 ;13 1059085

Mitochondrial genomic integrity and the nuclear epigenome in health and disease.

Amanda L Morin, Phyo W Win, Angela Z Lin, Christina A Castellani.

  Bidirectional crosstalk between the nuclear and mitochondrial genomes is essential for proper cell functioning. Mitochondrial DNA copy number (mtDNA-CN) and heteroplasmy influence mitochondrial function, which can influence the nuclear genome and contribute to health and disease. Evidence shows that mtDNA-CN and heteroplasmic variation are associated with aging, complex disease, and all-cause mortality. Further, the nuclear epigenome may mediate the effects of mtDNA variation on disease. In this way, mitochondria act as an environmental biosensor translating vital information about the state of the cell to the nuclear genome. Cellular communication between mtDNA variation and the nuclear epigenome can be achieved by modification of metabolites and intermediates of the citric acid cycle and oxidative phosphorylation. These essential molecules (e.g. ATP, acetyl-CoA, ɑ-ketoglutarate and S-adenosylmethionine) act as substrates and cofactors for enzymes involved in epigenetic modifications. The role of mitochondria as an environmental biosensor is emerging as a critical modifier of disease states. Uncovering the mechanisms of these dynamics in disease processes is expected to lead to earlier and improved treatment for a variety of diseases. However, the influence of mtDNA-CN and heteroplasmy variation on mitochondrially-derived epigenome-modifying metabolites and intermediates is poorly understood. This perspective will focus on the relationship between mtDNA-CN, heteroplasmy, and epigenome modifying cofactors and substrates, and the influence of their dynamics on the nuclear epigenome in health and disease.

Keywords:  DNA methylation; aging; disease; epigenome; histone acetylation; metabolism; mitochondrial DNA

DOI:  https://doi.org/10.3389/fendo.2022.1059085
Biochim Biophys Acta Gene Regul Mech. 2022 Nov 18. pii: S1874-9399(22)00115-8. [Epub ahead of print] 194900

Histone acetyltransferase 1 (HAT1) acetylates hypoxia-inducible factor 2 alpha (HIF2A) to execute hypoxia response.

Naveen Kumar, Mainak Mondal, B P Arathi, Nagalingam Ravi Sundaresan, Kumaravel Somasundaram.

  Hypoxic response to low oxygen levels is characteristic of most solid cancers. Hypoxia-inducible factors (HIFs) regulate cellular metabolism, survival, proliferation, and cancer stem cell growth during hypoxia. The genome-wide analysis identified HAT1, a type B histone acetyltransferase, as an upregulated and essential gene in glioblastoma (GBM). GSEA analysis of differentially regulated genes in HAT1 silenced cells identified significant depletion of "hypoxia" gene sets. Hypoxia conditions induced HIF2A, not HIF1A protein levels in glioma cells in a HAT1-dependent manner. HAT1 and HIF2A interacted with each other and occupied the promoter of VEGFA, a bonafide HIF1A/HIF2A target. Acetylation of K512 and K596 residues by HAT1 is essential for HIF2A stabilization under normoxia and hypoxia as HIF2A carrying acetylation mimic mutations at either of these residues (H512Q or K596Q) showed stable expression in HAT1 silenced cells under normoxia and hypoxia conditions. Finally, we demonstrate that the HAT1-HIF2A axis is essential for hypoxia-promoted cancer stem cell maintenance and reprogramming. Thus, our study identifies that the HAT1-dependent acetylation of HIF2A is vital to executing the hypoxia-induced cell survival and cancer stem cell growth, therefore proposing the HAT1-HIF2A axis as a potential therapeutic target.

Keywords:  Acetylation; GSCs; Glioblastoma; Glioma; HAT1; HIF2A; Hypoxia; Oncogene; Reprogramming; Ubiquitination; β-Catenin

DOI:  https://doi.org/10.1016/j.bbagrm.2022.194900
J Biol Chem. 2022 Nov 18. pii: S0021-9258(22)01163-2. [Epub ahead of print] 102720

Acetyl-CoA carboxylase 1 depletion suppresses de novo fatty acid synthesis and mitochondrial β-oxidation in castration-resistant prostate cancer cells.

Shaoyou Liu, Jiarun Lai, Yuanfa Feng, Yangjia Zhuo, Hui Zhang, Yupeng Chen, Jinchuang Li, Xinyue Mei, Yanting Zeng, Jiaming Su, Yulin Deng, Funeng Jiang, Shengbang Yang, Huijing Tan, Chi Tin Hon, Sun Wei, Zhaodong Han, Fen Wang, Weide Zhong.

  Cancer cells, including those of prostate cancer (PCa), often hijack intrinsic cell signaling to reprogram their metabolism. Part of this reprogramming includes the activation of de novo synthesis of fatty acids that not only serve as building blocks for membrane synthesis but also as energy sources for cell proliferation. However, how de novo fatty acid synthesis contributes to PCa progression is still poorly understood. Herein, by mining public datasets, we discovered that the expression of acetyl-CoA carboxylase alpha (ACACA), which encodes acetyl-CoA carboxylase 1 (ACC1), was highly expressed in human PCa. In addition, patients with high ACACA expression had a short disease-free survival time. We also reported that depletion of ACACA reduced de novo fatty acid synthesis and PI3K/AKT signaling in the human castration-resistant PCa (CRPC) cell lines DU145 and PC3. Furthermore, depletion of ACACA downregulates mitochondrial beta-oxidation, resulting in mitochondrial dysfunction, a reduction in ATP production, an imbalanced nicotinamide adenine dinucleotide phosphate (NADP+)/NADPhydrogen(H) ratio, increased reactive oxygen species (ROS), and therefore apoptosis. Reduced exogenous fatty acids by depleting lipid or lowering serum supplementation exacerbated both shRNA depletion and pharmacological inhibition of ACACA induced apoptosis in vitro. Collectively, our results suggest that inhibition of ectopic ACACA , together with suppression of exogenous fatty acid uptake, can be a novel strategy for treating currently incurable CRPC.

Keywords:  Prostate cancer; acetyl-CoA carboxylase 1; apoptosis; de novo fatty acid synthesis; energy stress; prognosis

DOI:  https://doi.org/10.1016/j.jbc.2022.102720