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Super-enhancer-driven MLX mediates redox balance maintanance via SLC7A11 in osteosarcoma

ABSTRACT: A systematic analysis of super-enhancers identified MLX as a potential oncogene in osteosarcoma. Knockdown of MLX impaired tumor aggressiveness in vitro and in vivo, suggesting oncogenic properties of MLX. Mechanistically, silencing of MLX downregulates SLC7A11, a key gene encoding glutamate/cystine antiporter, to attenuate the uptake of cystine and interrupt the redox balance, leading to ferroptotic cell death. Pharmacological inhibition of SLC7A11 triggered massive ferroptosis and caused impaired tumor growth, providing a promising approach for osteosarcoma treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220173 | GEO | 2023/08/08

REPOSITORIES: GEO

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Super-enhancer-driven MLX mediates redox balance maintanance via SLC7A11 in osteosarcoma

Project description:Super-enhancer-driven MLX mediates redox balance maintanance via SLC7A11 in osteosarcoma

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Chemerin attenuates acute kidney injury by inhibiting ferroptosis via the AMPK/NRF2/SLC7A11 axis

Project description:Acute kidney injury (AKI) is a common and life-threatening condition associated with cell death, where ferroptosis plays a critical role. Chemerin, primarily produced in white adipose tissue, has multiple biological functions in renal pathophysiology. However, to date, whether and how chemerin regulates the progression of AKI remain unclear. Here, we found that chemerin expression was reduced in both AKI model mice and cells. Similarly, serum chemerin levels were also decreased in AKI patients. The administration of recombinant chemerin improves renal function in ischemia-reperfusion (I/R) model mice. Chemerin significantly attenuates ferroptosis in kidneys. In TCMK-1 cells, chemerin knockdown further aggravates ferroptosis. Mechanistically, chemerin activates AMP-activated protein kinase (AMPK), which induces the phosphorylation of nuclear factor erythroid 2-related factor 2 (NRF2) in renal tubular cells. Subsequently, NRF2 translocates into the nucleus, where it stimulates the expression of cystine/glutamate antiporter solute carrier (SLC7A11). As a result, cystine uptake and glutathione (GSH) biosynthesis in renal tubular cells were increased, which confers cells with higher capacity against ferroptosis. Overall, our findings indicate that chemerin plays a protective role in AKI by repressing ferroptosis in renal tubular cells, which is likely due to the activation in the AMPK/NRF2/SLC7A11 axis.

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TRIB3 inhibition by palbociclib sensitizes prostate cancer to ferroptosis via SOX2-mediated SLC7A11 downregulation

Project description:Palbociclib is a CDK4/6 inhibitor approved for the treatment of breast cancer by suppressing cell proliferation. However, monotherapy with palbociclib was discouraging in prostate cancer, calling for a mechanism-based effective therapy. In this study, we reported in prostate cancer that palbociclib is a potent sensitizer of ferroptosis, which is worked out by downregulating the expression of TRIB3, a gene highly expressed in prostate cancer. Specifically, TRIB3 knockdown augmented the response of prostate cancer cells to ferroptosis inducers, whereas, TRIB3 overexpression rescued prostate cancer cells from palbociclib-induced ferroptosis. Mechanistically, TRIB3 inhibition by palbociclib resulted in downregulation of SOX2, which subsequently led to compromised expression of SLC7A11, a cystine/glutamate antiporter that counteracts ferroptosis. Functionally, a combined treatment of palbociclib with ferroptosis inducer significantly suppressed prostate cancer growth in a xenograft tumor model. Together, these results uncover an essential role of TRIB3/SOX2/SLC7A11 axis in palbociclib-induced ferroptosis, suggesting palbociclib a promising targeted therapy in combine with ferroptosis induction for the treatment of prostate cancer.

2024-10-31 | GSE273622 | GEO

MLX transcriptional regulation in muscle cells

Project description:This study set out to identify MLX transcriptional targets in muscle cells. C2C12 Myoblasts were virally transduced to increase MLX activity, by overexpression of the wild-type protein; and to decrease MLX activity by overexpression of a dominant negative MLX protein and by shRNA induced knockdown of MLX. Transcripts that were significantly and consistently regulated by the different modes of MLX modulation were identified. The largest proportion of these were genes encoding secreted proteins including growth factors, cytokines and extracellular proteins. We therefore conclude that MLX can regulate myokine transcripts. mRNA profiles from C2C12 muscle cells with increased and decreased MLX activity were examined.

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Transcriptional and genomic occupancy profiling from MLX WT and MLX knockout mouse tissues.

Project description:We generated mice null for MAX-like Protein X (MLX), encoded by Mlx. All male mice are sterile. We profiled testes tissue from WT versus KO mice by RNA-Seq. We performed ChIP-Seq on WT and KO testes for MLX and MAX, as well as ChIP-Seq for MLX and MAX from primary B220+ splenic B cells, and ChIP-Seq for MLX, MAX and MNT from 3T3 cell lines derived from WT and KO embryos.

2021-07-31 | GSE165820 | GEO

MLX transcriptional regulation in muscle cells

2016-01-04 | GSE70028 | GEO

The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

Project description:Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we find that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX, which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin like-growth factor-2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned media from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is conserved in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling.â??The data pproided are histome H4 acetlation data for MLX DN and MLX wt samples; 3 MLX DN H4 Ac Chip seq samples , 3 Inputs, 3 MLX WT H4 Ac samples and 3 WT inputs

2015-11-11 | E-GEOD-74678 | biostudies-arrayexpress

The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

Project description:Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we find that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX, which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin like-growth factor-2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned media from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is conserved in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling. The data pproided are histome H4 acetlation data for MLX DN and MLX wt samples;

2015-11-11 | GSE74678 | GEO

The Myc-Like Mlx Network Impacts Aging and Metabolism

Project description:The “Mlx” and “Myc” Networks share many common gene targets. Just as Myc’s activity depends upon its heterodimerization with Max, the Mlx Network requires that the Max-like factor Mlx associate with the Myc-like factors MondoA or ChREBP. We show here that body-wide Mlx inactivation, like that of Myc, accelerates numerous aging-related phenotypes pertaining to body habitus and metabolism. The deregulation of numerous aging-related Myc target gene sets is also accelerated. Among other functions, these gene sets often regulate ribosomal and mitochondrial structure and function, genomic stability and aging. Whereas “MycKO” mice have an extended lifespan because of a lower cancer incidence, “MlxKO” mice have normal lifespans and a somewhat higher cancer incidence. Like Myc, Mlx, MondoA and ChREBP expression and that of their target genes, deteriorate with age in both mice and humans, underscoring the importance of life-long and balanced cross-talk between the two Networks to maintain normal aging.

2024-10-10 | GSE248073 | GEO

Radiotherapy and IFNγ treatment effect on transcriptome in HT1080 cells

Project description:Immune checkpoint blockade is a powerful oncologic treatment modality for a wide variety of human malignancies. Randomized clinical trials are assessing how best to interdigitate this treatment modality with traditional therapies including radiotherapy. A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities including radiotherapy. Here, we demonstrate that radiotherapy induces tumor cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor cell ferroptosis. Mechanistically, IFN derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically repress SLC7A11, a unit of the glutamate-cystine antiporter xc-, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy.

2020-09-23 | GSE137946 | GEO

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