Ultraviolet A irradiation induces senescence in human dermal fibroblasts by down-regulating DNMT1 via ZEB1

Yi, Yuxin; Xie, Hongfu; Xiao, Xiao; Wang, Ben; Du, Rui; Liu, Yingzi; Li, Zibo; Wang, Jun; Sun, Lun‐Quan; Deng, Zhili; Li, Ji

doi:10.18632/aging.101383

Cited by 24 publications

(20 citation statements)

References 42 publications

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“…Particularly in untreated skin, this increase was striking, because normal epidermis displayed no detectable p16Ink4a expression, as observed also by others (21). Also the reduction of DNMT1 protein can be considered as a senescence marker as DNMT1 protein is decreased in senescent fibroblasts (11,22,23) and mouse keratinocytes (as previously discussed). Moreover, the inhibition of DNMT1 promotes senescence in these cells (11, 22, 23, s.a.).…”

Section: Discussionsupporting

confidence: 68%

Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation

Petersen

Mariscal

et al. 2019

Cancer Research

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Mice with a keratinocyte-restricted deletion of the actin polymerization-promoting molecule, N-WASP, display cyclic hair loss and skin inflammation. Here, we showed that these mice were also resistant to 7,12-dimethylbenz(a) anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor formation. This resistance correlated with decreased expression of the senescence regulator, DNMT1, and increased expression of the senescence marker, p16Ink4a, in N-WASP-deficient epidermis. Moreover, primary N-WASP-null keratinocytes displayed a premature senescence phenotype in vitro. Expression and activation of p53, a major inducer of senescence, was not significantly altered in N-WASP-null keratinocytes. However, impairment of p53 function effectively rescued the senescence phenotype, indicating that N-WASP was an inhibitor of p53-induced senescence. Mechanistically, N-WASP regulated senescence by preventing p53-dependent degradation of the H3K9 methyltransferases, G9a/GLP, and the DNA methyltransferase, DNMT1, which both control keratinocyte senescence. This pathway collaborated with other N-WASP-independent, senescence-promoting signaling downstream of p53 and allowed the fine tuning of p53induced senescence by N-WASP. Collectively, these data reveal N-WASP as an inhibitor of p53-induced senescence, which might be of importance for skin tumor formation and cellular aging of keratinocytes.Significance: These findings demonstrate that N-WASP regulates p53-dependent senescence in keratinocytes in vitro and in vivo. Gene expression analysisRNA from skin and keratinocytes culture was prepared using the GeneElute Mammalian Total RNA Miniprep Kit (RNT350, Sigma) according to the instructions of the manufacturer. Skin Li et al.

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Section: Discussionsupporting

confidence: 68%

Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation

Petersen

Mariscal

et al. 2019

Cancer Research

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“…In support of this data interpretation, we found the upregulation of the oxidative phosphorylation enzymes in both types of analyses (Tables 3A and 3B ), and the hallmarks of reactive oxygen species pathways and peroxisome associated with ZEB1 HD class (Table 3A ). This is of particular interest as ZEB1 is indeed involved in ROS-induced cellular response as a crucial target of the miR-200 family members that are upregulated under oxidative stress conditions 37 – 41 .…”

Section: Resultsmentioning

confidence: 99%

Loss of the candidate tumor suppressor ZEB1 (TCF8, ZFHX1A) in Sézary syndrome

et al. 2018

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Cutaneous T-cell lymphoma is a group of incurable extranodal non-Hodgkin lymphomas that develop from the skin-homing CD4+ T cell. Mycosis fungoides and Sézary syndrome are the most common histological subtypes. Although next-generation sequencing data provided significant advances in the comprehension of the genetic basis of this lymphoma, there is not uniform consensus on the identity and prevalence of putative driver genes for this heterogeneous group of tumors. Additional studies may increase the knowledge about the complex genetic etiology characterizing this lymphoma. We used SNP6 arrays and GISTIC algorithm to prioritize a list of focal somatic copy-number alterations in a dataset of multiple sequential samples from 21 Sézary syndrome patients. Our results confirmed a prevalence of significant focal deletions over amplifications: single well-known tumor suppressors, such as TP53, PTEN, and RB1, are targeted by these aberrations. In our cohort, ZEB1 (TCF8, ZFHX1A) spans a deletion having the highest level of significance. In a larger group of 43 patients, we found that ZEB1 is affected by deletions and somatic inactivating mutations in 46.5% of cases; also, we found potentially relevant ZEB1 germline variants. The survival analysis shows a worse clinical course for patients with ZEB1 biallelic inactivation. Multiple abnormal expression signatures were found associated with ZEB1 depletion in Sézary patients we verified that ZEB1 exerts a role in oxidative response of Sézary cells. Our data confirm the importance of deletions in the pathogenesis of cutaneous T-cell lymphoma. The characterization of ZEB1 abnormalities in Sézary syndrome fulfils the criteria of a canonical tumor suppressor gene. Although additional confirmations are needed, our findings suggest, for the first time, that ZEB1 germline variants might contribute to the risk of developing this disease. Also, we provide evidence that ZEB1 activity in Sézary cells, influencing the reactive oxygen species production, affects cell viability and apoptosis.

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“…We and other research groups have demonstrated that chronic repetitive UVA radiation as well as a single high dose of UVA radiation causes cellular senescence in vitro and contributes to the induction of skin photo-aging in vivo, mostly by the generation of ROS [19,29], particularly H 2 O 2 , which has a long half-life compared with O 2 − and 1 O 2 . To induce biological reactions in the skin, UVA radiation is absorbed by molecules, called endogenous and exogenous chromophores, such as flavins, porphyrins, pterins, urocanic acid, FICZ, heme-oxygenase-1, and NADPH-oxidase.…”

Section: Discussionmentioning

confidence: 97%

Riboflavin Plays a Pivotal Role in the UVA-Induced Cytotoxicity of Fibroblasts as a Key Molecule in the Production of H2O2 by UVA Radiation in Collaboration with Amino Acids and Vitamins

Yoshimoto

Kohara

Sato

et al. 2020

IJMS

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To investigate environmental factors that contribute to ultraviolet A (UVA)-induced oxidative stress, which accelerates the senescence and toxicity of skin cells, we irradiated human fibroblasts cultured in commonly used essential media with UVA and evaluated their viability and production of reactive oxygen species. The viability of fibroblasts exposed to a single dose of 3.6 J/cm2 UVA was not reduced when cultured in Hanks balanced salt solution, but it was significantly decreased when cultured in Dulbecco’s modified Eagle’s medium (DMEM), which contains various amino acids and vitamins. Furthermore, cell viability was not reduced when fibroblasts were cultured in DMEM and treated with a hydrogen peroxide (H2O2) scavenger such as glutathione or catalase added after UVA irradiation. In addition, we confirmed that the production of H2O2 was dramatically increased by UVA photosensitization when riboflavin (R) coexisted with amino acids such as tryptophan (T), and found that R with folic acid (F) produced high levels of H2O2 after UVA irradiation. Furthermore, we noticed that R and F or R and T have different photosensitization mechanisms since NaN3, which is a singlet oxygen quencher, suppressed only R and T photosensitization. Lastly, we examined the effects of antioxidants (L-ascorbic acid, trolox, L-cysteine, and L-histidine), which are singlet oxygen or superoxide or H2O2 scavengers, on R and F or on R and T photosensitization, and found that 1 mM ascorbic acid, Trolox, and L-histidine were strongly photosensitized with R, and produced significant levels of H2O2 during UVA exposure. However, 1 mM L-cysteine dramatically suppressed H2O2 production by UVA photosensitization. These data suggest that a low concentration of R-derived photosensitization is elicited by different mechanisms depending on the coexisting vitamins and amino acids, and regulates cellular oxidative stress by producing H2O2 during UVA exposure.

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Ultraviolet A irradiation induces senescence in human dermal fibroblasts by down-regulating DNMT1 via ZEB1

Cited by 24 publications

References 42 publications

Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation

Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation

Loss of the candidate tumor suppressor ZEB1 (TCF8, ZFHX1A) in Sézary syndrome

Riboflavin Plays a Pivotal Role in the UVA-Induced Cytotoxicity of Fibroblasts as a Key Molecule in the Production of H2O2 by UVA Radiation in Collaboration with Amino Acids and Vitamins

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