Histone H2AX promotes neuronal health by controlling mitochondrial homeostasis

Weyemi, Urbain; Paul, Bindu D.; Bhattacharya, Deeya; Malla, Adarsha P.; Boufraqech, Myriem; Harraz, Maged M.; Bonner, William M.; Snyder, Solomon H.

doi:10.1073/pnas.1820245116

Cited by 30 publications

(11 citation statements)

References 35 publications

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“…Above results indicated that ASH could induce DNA double strand breaks in HepG2 cells and trigger subsequent apoptotic cell death. When a double-strand break occurs in DNA, a sequence of events occurs in which the H2A histone family member X (H2AX) becomes phosphorylated on serine 139 [23,26]. Thus, we detected the expression of phospho-H2A.X-Ser139 and H2A.X to further confirm ASH induced DNA damage.…”

Section: Resultsmentioning

confidence: 95%

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

Hong

et al. 2019

Cells

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The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown strong and explicit cancer cell-selectivity, which results in little toxicity toward normal tissues, and has been recognized as a potential, relatively safe anticancer agent. However, several cancers are resistant to the apoptosis induced by TRAIL. A recent study found that shikonin b (alkannin, 5,8-dihydroxy-2-[(1S)-1-hydroxy-4-methylpent-3-en-1-yl]naphthalene-1,4-dione) might induce apoptosis in TRAIL-resistant cholangiocarcinoma cells through reactive oxygen species (ROS)-mediated caspases activation. However, the strong cytotoxic activity has limited its potential as an anticancer drug. Thus, the current study intends to discover novel shikonin derivatives which can sensitize the liver cancer cell to TRAIL-induced apoptosis while exhibiting little toxicity toward the normal hepatic cell. The trypan blue exclusion assay, western blot assay, 4′,6-diamidino-2-phenylindole (DAPI) staining and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay as well as the ‘comet’ assay, were used to study the underlying mechanisms of cell death and to search for any mechanisms of an enhancement of TRAIL-mediated apoptosis in the presence of ASH. Herein, we demonstrated that non-cytotoxic doses of acetylshikonin (ASH), one of the shikonin derivatives, in combination with TRAIL, could promote apoptosis in HepG2 cells. Further studies showed that application of ASH in a non-cytotoxic dose (2.5 μM) could increase intracellular ROS production and induce DNA damage, which might trigger a cell intrinsic apoptosis pathway in the TRAIL-resistant HepG2 cell. Combination treatment with a non-cytotoxic dose of ASH and TRAIL activated caspase and increased the cleavage of PARP-1 in the HepG2 cell. However, when intracellular ROS production was suppressed by N-acetyl-l-cysteine (NAC), the synergistic effects of ASH and TRAIL on hepatocellular carcinoma (HCC) cell apoptosis was abolished. Furthermore, NAC could alleviate p53 and the p53 upregulated modulator of apoptosis (PUMA) expression induced by TRAIL and ASH. Small (or short) interfering RNA (siRNA) targeting PUMA or p53 significantly reversed ASH-mediated sensitization to TRAIL-induced apoptosis. In addition, Bax gene deficiency also abolished ASH-induced TRAIL sensitization. An orthotopical HCC implantation mice model further confirmed that co-treated ASH overcomes TRAIL resistance in HCC cells without exhibiting potent toxicity in vivo. In conclusion, the above data suggested that ROS could induce DNA damage and activating p53/PUMA/Bax signaling, and thus, this resulted in the permeabilization of mitochondrial outer membrane and activating caspases as well as sensitizing the HCC cell to apoptosis induced by TRAIL and ASH treatment.

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Section: Resultsmentioning

confidence: 95%

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

Hong

et al. 2019

Cells

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“…Although phosphorylation of H2AX is an initial step in DDR, the histone has also been implicated in cell proliferation and apoptosis (see Introduction), and, very recently, in the support of neuronal maintenance via controlling mitochondrial homeostasis [ 35 ]. Given the pleiotropic effects of the molecule—and considering that the links between cell proliferation and apoptosis in adult and old neurogenesis are quite complex [ 15 ]—we have split our discussion to first consider the γH2AX/cCASP3 response to irradiation, a well-established DNA damaging event, and then the presence of the two molecules in the normal aging brain.…”

Section: Discussionmentioning

confidence: 99%

Association of Caspase 3 Activation and H2AX γ Phosphorylation in the Aging Brain: Studies on Untreated and Irradiated Mice

et al. 2021

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Phosphorylation of H2AX is a response to DNA damage, but γH2AX also associates with mitosis and/or apoptosis. We examined the effects of X-rays on DNA integrity to shed more light on the significance of H2AX phosphorylation and its relationship with activation of caspase 3 (CASP3), the main apoptotic effector. After administration of the S phase marker BrdU, brains were collected from untreated and irradiated (10 Gray) 24-month-old mice surviving 15 or 30 min after irradiation. After paraffin embedding, brain sections were single- or double-stained with antibodies against γH2AX, p53-binding protein 1 (53BP1) (which is recruited during the DNA damage response (DDR)), active CASP3 (cCASP3), 5-Bromo-2-deoxyuridine (BrdU), and phosphorylated histone H3 (pHH3) (which labels proliferating cells). After statistical analysis, we demonstrated that irradiation not only induced a robust DDR with the appearance of γH2AX and upregulation of 53BP1 but also that cells with damaged DNA attempted to synthesize new genetic material from the rise in BrdU immunostaining, with increased expression of cCASP3. Association of γH2AX, 53BP1, and cCASP3 was also evident in normal nonirradiated mice, where DNA synthesis appeared to be linked to disturbances in DNA repair mechanisms rather than true mitotic activity.

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“…These results show that TMS may have induced DNA damage and consequent apoptosis in 143B cells. H2AX is phosphorylated on serine 139 and is then designated as γ H2AX in a reaction involving DNA double-strand breaks [ 24 , 25 ]. Therefore, the expression of H2AX and phosphorylation of H2AX-Ser139 were examined to confirm that treatment with TMS induced DNA damage in 143B cells.…”

Section: Resultsmentioning

confidence: 99%

Resveratrol Derivative, Trans‐3, 5, 4 ^′‐Trimethoxystilbene Sensitizes Osteosarcoma Cells to Apoptosis via ROS‐Induced Caspases Activation

Feng

Clayton

Yake

et al. 2021

Oxidative Medicine and Cellular Longevity

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Numerous studies have shown that resveratrol can induce apoptosis in cancer cells. Trans-3, 5, 4 ′ -trimethoxystilbene (TMS), a novel derivative of resveratrol, is a more potent anticancer compound than resveratrol and can induce apoptosis in cancer cells. Herein, we examined the mechanisms involved in TMS-mediated sensitization of human osteosarcoma (143B) cells to TNF-related apoptosis-inducing ligand- (TRAIL-) induced apoptosis. Our results showed that cotreatment with TSM and TRAIL activated caspases and increased PARP-1 cleavage in 143B cells. Decreasing cellular ROS levels using NAC reversed TSM- and TRAIL-induced apoptosis in 143B cells. NAC abolished the upregulated expression of PUMA and p53 induced by treatment with TRAIL and TSM. Silencing the expression of p53 or PUMA using RNA interference attenuated TSM-mediated sensitization of 143B cells to TRAIL-induced apoptosis. Knockdown of Bax also reversed TSM-induced sensitization of 143B cell to TRAIL-mediated apoptotic cell death. These results indicate that cotreatment with TRAIL and TSM evaluated intracellular ROS level, promoted DNA damage, and activated the Bax/PUMA/p53 pathway, leading to activation of both mitochondrial and caspase-mediated apoptosis in 143B cells. Orthotopic implantation of 143B cells in mice also demonstrated that cotreatment with TRAIL and TSM reversed resistance to apoptosis in cells without obvious adverse effects in normal cells.

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Histone H2AX promotes neuronal health by controlling mitochondrial homeostasis

Cited by 30 publications

References 35 publications

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

Association of Caspase 3 Activation and H2AX γ Phosphorylation in the Aging Brain: Studies on Untreated and Irradiated Mice

Resveratrol Derivative, Trans‐3, 5, 4 ^′‐Trimethoxystilbene Sensitizes Osteosarcoma Cells to Apoptosis via ROS‐Induced Caspases Activation

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Histone H2AX promotes neuronal health by controlling mitochondrial homeostasis

Cited by 30 publications

References 35 publications

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

Association of Caspase 3 Activation and H2AX γ Phosphorylation in the Aging Brain: Studies on Untreated and Irradiated Mice

Resveratrol Derivative, Trans‐3, 5, 4 ′‐Trimethoxystilbene Sensitizes Osteosarcoma Cells to Apoptosis via ROS‐Induced Caspases Activation

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Resveratrol Derivative, Trans‐3, 5, 4 ^′‐Trimethoxystilbene Sensitizes Osteosarcoma Cells to Apoptosis via ROS‐Induced Caspases Activation