bims-meprid 2024-12-01 papers

bims-meprid

Biomed News

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2024–12–01
five papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Nucleo-cytosolic acetyl-CoA drives tumor immune evasion by regulating PD-L1 in melanoma.
ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.
LDHB Mediates Histone Lactylation to Activate PD-L1 and Promote Ovarian Cancer Immune Escape.
Interplay between epigenetics, senescence and cellular redox metabolism in cancer and its therapeutic implications.
The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.

Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01366-4. [Epub ahead of print]43(12): 115015

Nucleo-cytosolic acetyl-CoA drives tumor immune evasion by regulating PD-L1 in melanoma.

Huina Wang, Xiuli Yi, Xiangxu Wang, Yuqi Yang, Hengxiang Zhang, Hao Wang, Jianru Chen, Baolu Zhang, Sen Guo, Lili Wu, Juan Du, Yuhan Chen, Ningyue Sun, Tianwen Gao, Rui Zhang, Huijie Bian, Lintao Jia, Chunying Li, Weinan Guo.

  Acetyl coenzyme A (acetyl-CoA), a versatile central metabolite, plays a critical role in various metabolic processes and protein acetylation. While its impact on tumor cell properties is well established, the connection between acetyl-CoA metabolism and immune evasion in tumors remains unclear. Here, we uncover a mechanism by which nucleo-cytosolic acetyl-CoA contributes to immune evasion through regulation of programmed death ligand 1 (PD-L1). Specifically, bioinformatics analysis reveals a negative correlation between acetyl-CoA metabolism and anti-tumor immunity across multiple cancers. Inhibition of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) leads to a re-invigoration of cytotoxic T cells and enhances the efficacy of immunotherapy. Mechanistically, nucleo-cytosolic acetyl-CoA promotes PD-L1 transcription via P300-dependent histone H3K27 acetylation at the promoter region of CD274. The ACLY-H3K27ac-PD-L1 axis is verified in clinical specimens and predicts poor immunotherapy response. Our findings suggest that targeting acetyl-CoA metabolism may act as a promising strategy to overcome immune evasion and improve the outcomes of cancer immunotherapy.

Keywords:  ACLY; Acetyl-CoA; CP: Cancer; PD-L1; histone acetylation; immune evasion; melanoma; metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.115015
Cell Rep. 2024 Nov 21. pii: S2211-1247(24)01339-1. [Epub ahead of print]43(12): 114988

ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.

Sabina I Hlavaty, Kelsey N Salcido, Katherine A Pniewski, Dzmitry Mukha, Weili Ma, Toshitha Kannan, Joel Cassel, Yellamelli V V Srikanth, Qin Liu, Andrew Kossenkov, Joseph M Salvino, Qing Chen, Zachary T Schug.

  Cancer cells often use alternative nutrient sources to support their metabolism and proliferation. One important alternative nutrient source for many cancers is acetate. Acetate is metabolized into acetyl-coenzyme A (CoA) by acetyl-CoA synthetases 1 and 2 (ACSS1 and ACSS2), which are found in the mitochondria and cytosol, respectively. We show that ACSS1 and ACSS2 are differentially expressed in cancer. Melanoma, breast cancer, and acute myeloid leukemia cells expressing ACSS1 readily use acetate for acetyl-CoA biosynthesis and to fuel mitochondrial metabolism. ACSS1-dependent acetate metabolism decreases the relative contributions of glucose and glutamine to the tricarboxylic acid (TCA) cycle and alters the pentose phosphate pathway and redox state of cancer cells. ACSS1 knockdown decreases acute myeloid leukemia burden in vivo and inhibits melanoma tumor and metastatic growth. Our study highlights a key role for ACSS1-dependent acetate metabolism for cancer growth, raising the potential for ACSS1-targeting therapies in cancer.

Keywords:  ACSS1; ACSS2; ACSS2 inhibitor; AML; CP: Cancer; CP: Metabolism; acetate; cancer; melanoma; metabolism; metastasis

DOI:  https://doi.org/10.1016/j.celrep.2024.114988
Cancer Invest. 2024 Nov 25. 1-10

LDHB Mediates Histone Lactylation to Activate PD-L1 and Promote Ovarian Cancer Immune Escape.

Xuemei Hu, Zhenqiang Huang, Lingyun Li.

   BACKGROUND: To investigate the effects of LDHB on lactylation of programmed cell death 1 ligand (PD-L1) and immune evasion of ovarian cancer.
METHODS: Ovarian cancer cells were transfected with LDHB siRNA and cultured with primed T cells. Cell proliferation and viability were measured by cell counting kit 8 (CCK-8) and colony formation assay. The production of immune factors was detected by enzyme-linked immunosorbent assay (ELISA). The histone lactylation and activity of PD-L1 promoter were measured by chromatin immunoprecipitation (ChIP)-qPCR assay and luciferase reporter gene assay, respectively.
RESULTS: Knockdown of LDHB notably inhibited the growth, glucose uptake, lactate production, and ATP production of ovarian cancer cells. Knockdown of LDHB enhanced the killing effects of T cells, led to increased production of immune activation factors IL-2, TNF-α, and IFN-γ, as well as elevated the levels of granzyme B and perforin. Mechanical study identified that LDHB regulated the H3K18 lactylation (H3K18la) modification on PD-L1 promoter region to promote its expression. Overexpression of PD-L1 abolished the immune activation effects that induced by siLDHB.
CONCLUSION: The LDHB modulated lactate production and the histone lactylation on PD-L1 promoter, which ultimately regulated its expression and participated in the immune evasion of ovarian cancer cells.

Keywords:  Ovarian cancer; PD-L1; immune activation; lactate dehydrogenase B; lactylation

DOI:  https://doi.org/10.1080/07357907.2024.2430283
Redox Biol. 2024 Nov 23. pii: S2213-2317(24)00419-1. [Epub ahead of print]78 103441

Interplay between epigenetics, senescence and cellular redox metabolism in cancer and its therapeutic implications.

Geoffrey Balamurli, Angeline Qiu Xia Liew, Wee Wei Tee, Shazib Pervaiz.

  There is accumulating evidence indicating a close crosstalk between key molecular events regulating cell growth and proliferation, which could profoundly impact carcinogenesis and its progression. Here we focus on reviewing observations highlighting the interplay between epigenetic modifications, irreversible cell cycle arrest or senescence, and cellular redox metabolism. Epigenetic alterations, such as DNA methylation and histone modifications, dynamically influence tumour transcriptome, thereby impacting tumour phenotype, survival, growth and spread. Interestingly, the acquisition of senescent phenotype can be triggered by epigenetic changes, acting as a double-edged sword via its ability to suppress tumorigenesis or by facilitating an inflammatory milieu conducive for cancer progression. Concurrently, an aberrant redox metabolism, which is a function of the balance between reactive oxygen species (ROS) generation and intracellular anti-oxidant defences, influences signalling cascades and genomic stability in cancer cells by serving as a critical link between epigenetics and senescence. Recognizing this intricate interconnection offers a nuanced perspective for therapeutic intervention by simultaneously targeting specific epigenetic modifications, modulating senescence dynamics, and restoring redox homeostasis.

Keywords:  Cancer; Epigenetic modifications; Redox status; SASP; Senescence

DOI:  https://doi.org/10.1016/j.redox.2024.103441
Nat Commun. 2024 Nov 23. 15(1): 10163

The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.

Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens O Watzlawik, Yin Maggie Chen, Ariel L Raybuck, Daniel D Billadeau, Virginia Smith Shapiro, Wolfdieter Springer, Jie Sun, Mark R Boothby, Hu Zeng.

Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.

DOI: https://doi.org/10.1038/s41467-024-54344-5