Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase

Chang, Kai-Ming; Hsu, Todd; Hsu, Che Chia; Tsai, Shan Yin; Liu, Jr Jiun; Chou, Shao Wen; Liu, Ming-Sheng; Liou, Jing Ping; Ko, Chiung Yuan; Chen, Kai Yun; Hung, Jan Jong; Chang, Wen Chang; Chuang, Cheng Keng; Kao, Tzu-Jen; Chuang, Jian Ying

doi:10.1016/j.redox.2017.08.005

Cited by 58 publications

(63 citation statements)

References 45 publications

(56 reference statements)

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“…We found that SNHG12 is activated by the transcription factor, SP1. SP1 has been reported to play an important role in acquired TMZ resistance in GBM [39,40], and our results revealed that SP1 activated the transcription of SNHG12. Moreover, loss of DNA methylation made the promoter of SNHG12 more accessible to this transcription factor.…”

Section: Discussionsupporting

confidence: 70%

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

et al. 2020

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Background: Accumulating evidence shows that long noncoding RNAs (lncRNAs) are important regulator molecules involved in diverse biological processes. Acquired drug resistance is a major challenge in the clinical treatment of glioblastoma (GBM), and lncRNAs have been shown to play a role in chemotherapy resistance. However, the underlying mechanisms by which lncRNA mediates TMZ resistance in GBM remain poorly characterized. Methods: Quantitative reverse transcription PCR (qRT-PCR) and fluorescence in situ hybridization assays were used to detect small nucleolar RNA host gene 12 (SNHG12) levels in TMZ-sensitive and TMZ-resistant GBM cells and tissues. The effects of SNHG12 on TMZ resistance were investigated through in vitro assays (western blots, colony formation assays, flow cytometry assays, and TUNEL assays). The mechanism mediating the high expression of SNHG12 in TMZ-resistant cells and its relationships with miR-129-5p, mitogen-activated protein kinase 1 (MAPK1), and E2F transcription factor 7 (E2F7) were determined by bioinformatic analysis, bisulfite amplicon sequencing, methylation-specific PCR, dual luciferase reporter assays, chromatin immunoprecipitation assays, RNA immunoprecipitation assays, immunofluorescence, qRT-PCR, and western blot. For in vivo experiments, an intracranial xenograft tumor mouse model was used to investigate SNHG12 function. Results: SNHG12 was upregulated in TMZ-resistant cells and tissues. Overexpression of SNHG12 led to the development of acquired TMZ resistance, while knockdown of SNHG12 restored TMZ sensitivity. An abnormally low level of DNA methylation was detected within the promoter region of SNHG12, and loss of DNA methylation made this region more accessible to the Sp1 transcription factor (SP1); this indicated that methylation and SP1 work together to regulate SNHG12 expression. In the cytoplasm, SNHG12 served as a sponge for miR-129-5p, leading to upregulation of MAPK1 and E2F7 and endowing the GBM cells with TMZ resistance. Disinhibition of MAPK1 regulated TMZ-induced cell apoptosis and the G1/S cell cycle transition by activating the MAPK/ERK pathway, while E2F7 dysregulation was primarily associated with G1/S cell cycle transition. Clinically, SNHG12 overexpression was associated with poor survival of GBM patients undergoing TMZ treatment. Conclusion: Our results suggest that SNHG12 could serve as a promising therapeutic target to surmount TMZ resistance, thereby improving the clinical efficacy of TMZ chemotherapy.

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Section: Discussionsupporting

confidence: 70%

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

et al. 2020

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“…Our previous studies showed that Sp1 expression is upregulated in high-grade brain tumors, and is significantly higher in TMZ-resistant cells than in parental GBM cells; however, inhibition of Sp1 protein expression restores the inhibitory effects of TMZ in malignant GBM cells [17][18][19]. Thus, we next determined whether BA treatment affected Sp1 expression in parental control ( Figure 3A) and TMZ-resistant ( Figure 3B) GBM cells.…”

Section: Ba Suppresses Gbm Cell Growth Via Inhibition Of Sp1 Expressionmentioning

confidence: 93%

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

Hsu

Yang

et al. 2020

Cancers

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Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant origin, can cross the blood–brain barrier. Here, we investigated the antitumor effects of BA on typical glioblastoma cell lines and primary glioblastoma cells from patients, as well as corresponding temozolomide-resistant cells. Our findings verified that BA significantly reduced growth in all examined cells. Furthermore, gene-expression array analysis showed that the unfolded-protein response was significantly affected by BA. Moreover, BA treatment increased activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptotic pathway, and reduced specificity protein 1 (Sp1) expression. However, Sp1 overexpression reversed the observed cell-growth inhibition and PERK/CHOP signaling activation induced by BA. Because temozolomide-resistant cells exhibited significantly increased Sp1 expression, we concluded that Sp1-mediated PERK/CHOP signaling inhibition protects glioblastoma against cancer therapies; hence, BA treatment targeting this pathway can be considered as an effective therapeutic strategy to overcome such chemoresistance and tumor relapse.

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“…The degradation of DEPTOR is mainly controlled by β-TrCP, which gives us a clue that the dysregulation of β-TrCP directly affects the response of patients to chemotherapeutic agents (86). Sp1, specificity protein 1, is another agent enhances temozolomide resistance in glioblastoma (87). Doxorubixin stimulus causes the high expression of β-TrCP in breast cancer cell line MCF-7, which promoted Sp1 degradation.…”

Section: Other F-box Proteins Involved In Chemoresistancementioning

confidence: 99%

F‑box proteins involved in cancer‑associated drug resistance (Review)

et al. 2018

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The ubiquitin proteasome system (UPS) regulated human biological processes through the appropriate and efficient proteolysis of cellular proteins. F-box proteins are the vital components of SKP1-CUL1-FBP (SCF)-type E3 ubiquitin ligases that determine substrate specificity. As F-box proteins have the ability to control the degradation of several crucial protein targets associated with drug resistance, the dysregulation of these proteins may lead to induction of chemoresistance in cancer cells. Chemotherapy is one of the most conventional therapeutic approaches of treatment of patients with cancer. However, its exclusive application in clinical settings is restricted due to the development of chemoresistance, which typically results treatment failure. Therefore, overcoming drug resistance is considered as one of the most critical issues that researchers and clinician associated with oncology face. The present review serves to provide a comprehensive overview of F-box proteins and their possible targets as well as their correlation with the chemoresistance and chemosensitization of cancer cells. The article also presents an integrated representation of the complex regulatory mechanisms responsible for chemoresistance, which may lay the foundation to explore sensible candidate drugs for therapeutic intervention.

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Specificity protein 1-modulated superoxide dismutase 2 enhances temozolomide resistance in glioblastoma, which is independent of O6-methylguanine-DNA methyltransferase

Cited by 58 publications

References 45 publications

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

F‑box proteins involved in cancer‑associated drug resistance (Review)

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