Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics

Chianese, Ugo; Papulino, Chiara; Passaro, Eugenia; Evers, Tom M J; Babaei, Mehrad; Toraldo, Antonella; Marchi, Tommaso De; Niméus, Emma; Carafa, Vincenzo; Nicoletti, Maria Maddalena; Gaudio, Nunzio Del; Iaccarino, Nunzia; Randazzo, Antonio; Rotili, Dante; Mai, Antonello; Cappabianca, Salvatore; Mashaghi, Alireza; Altucci, Lucia; Benedetti, Rosaria

doi:10.1016/j.molmet.2022.101561

Cited by 4 publications

(2 citation statements)

References 77 publications

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“…To assess the metabolic status of the cells, we used a Seahorse XF24 Analyzer (Agilent Technologies, Santa Clara, CA, USA) with standard 24-well Seahorse microplates, as previously described [ 23 ]. To measure the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), a Mito Stress Test kit (Agilent Technologies, #103,015) was used after treatment of 6 h with 25 μM SCIC2.1.…”

Section: Methodsmentioning

confidence: 99%

SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism

Varghese,

Chianese,

Capasso

et al. 2023

J Transl Med

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Background Cancer cells are characterized by uncontrolled cell proliferation and impaired bioenergetics. Sirtuins are a family of highly conserved enzymes that play a fundamental role in energy metabolism regulation. SIRT1, in particular, drives many physiological stress responses and metabolic pathways following nutrient deprivation. We previously showed that SIRT1 activation using SCIC2.1 was able to attenuate genotoxic response and senescence. Here, we report that in hepatocellular carcinoma (HCC) cells under glucose-deprived conditions, SCIC2.1 treatment induced overexpression of SIRT1, SIRT3, and SIRT6, modulating metabolic response. Methods Flow cytometry was used to analyze the cell cycle. The MTT assay and xCELLigence system were used to measure cell viability and proliferation. In vitro enzymatic assays were carried out as directed by the manufacturer, and the absorbance was measured with an automated Infinite M1000 reader. Western blotting and immunoprecipitation were used to evaluate the expression of various proteins described in this study. The relative expression of genes was studied using real-time PCR. We employed a Seahorse XF24 Analyzer to determine the metabolic state of the cells. Oil Red O staining was used to measure lipid accumulation. Results SCIC2.1 significantly promoted mitochondrial biogenesis via the AMPK-p53-PGC1α pathway and enhanced mitochondrial ATP production under glucose deprivation. SIRT1 inhibition by Ex-527 further supported our hypothesis that metabolic effects are dependent on SIRT1 activation. Interestingly, SCIC2.1 reprogrammed glucose metabolism and fatty acid oxidation for bioenergetic circuits by repressing de novo lipogenesis. In addition, SCIC2.1-mediated SIRT1 activation strongly modulated antioxidant response through SIRT3 activation, and p53-dependent stress response via indirect recruitment of SIRT6. Conclusion Our results show that SCIC2.1 is able to promote energy homeostasis, attenuating metabolic stress under glucose deprivation via activation of SIRT1. These findings shed light on the metabolic action of SIRT1 in the pathogenesis of HCC and may help determine future therapies for this and, possibly, other metabolic diseases.

show abstract

Section: Methodsmentioning

confidence: 99%

SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism

Varghese,

Chianese,

Capasso

et al. 2023

J Transl Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…To assess the metabolic status of the cells, we used a Seahorse XF24 Analyzer (Agilent Technologies, Santa Clara, CA, USA) with standard 24-well Seahorse microplates, as previously described (23). To measure the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), a Mito Stress Test kit (Agilent Technologies, #103015) was used after treatment with SCIC2.1 at the indicated concentration.…”

Section: Cellular Mitochondrial Stress and Atp Productionmentioning

confidence: 99%

SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism

Varghese

Chianese

Capasso

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Background Cancer cells are characterized by uncontrolled cell proliferation and impaired bioenergetics. Sirtuins are a family of highly conserved enzymes that play a fundamental role in energy metabolism regulation. SIRT1, in particular, drives many physiological stress responses and metabolic pathways following nutrient deprivation. We previously showed that SIRT1 activation using SCIC2.1 was able to attenuate genotoxic response and senescence. Here, we report that in hepatocellular carcinoma (HCC) cells under glucose-deprived conditions, SCIC2.1 treatment induced overexpression of SIRT1, SIRT3, and SIRT6, modulating metabolic response. Methods Flow cytometry was used to analyze the cell cycle. The MTT assay and xCELLigence system were used to measure cell viability and proliferation. In vitro enzymatic assays were carried out as directed by the manufacturer, and the absorbance was measured with an automated Infinite M1000 reader. Western blotting and immunoprecipitation were used to evaluate the expression of various proteins described in this study. The relative expression of genes was studied using real-time PCR. We employed a Seahorse XF24 Analyzer to determine the metabolic state of the cells. Oil Red O staining was used to measure lipid accumulation. Results SCIC2.1 significantly promoted mitochondrial biogenesis via the AMPK-p53-PGC1α pathway and enhanced mitochondrial ATP production under glucose deprivation. SIRT1 inhibition by EX-527 further supported our hypothesis that metabolic effects are dependent on SIRT1 activation. Interestingly, SCIC2.1 reprogrammed glucose metabolism and fatty acid oxidation for bioenergetic circuits by repressing de novo lipogenesis. In addition, SCIC2.1-mediated SIRT1 activation strongly modulated antioxidant response through SIRT3 activation, and p53-dependent stress response via indirect recruitment of SIRT6. Conclusion Our results show that SCIC2.1 is able to promote energy homeostasis, attenuating metabolic stress under glucose deprivation via activation of SIRT1. These findings shed light on the metabolic action of SIRT1 in the pathogenesis of HCC and may help determine future therapies for this and, possibly, other metabolic diseases.

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The role of lysine-specific demethylase 6A (KDM6A) in tumorigenesis and its therapeutic potentials in cancer therapy

Chen

Zhong

et al. 2023

Bioorganic Chemistry

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Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics

Cited by 4 publications

References 77 publications

SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism

SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism

SIRT1 activation promotes energy homeostasis and reprograms liver cancer metabolism

The role of lysine-specific demethylase 6A (KDM6A) in tumorigenesis and its therapeutic potentials in cancer therapy

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