Impact of H3K27 Demethylase Inhibitor GSKJ4 on NSCLC Cells Alone and in Combination with Metformin

Watarai, Hikaru; Okada, Masashi; Kuramoto, Kenta; Takeda, Hiroyuki; Sakaki, Hirotsugu; Seino, Shizuka; Oizumi, Hiroyuki; Sadahiro, Mitsuaki; Kitanaka, Chifumi

doi:10.21873/anticanres.11198

Cited by 28 publications

(34 citation statements)

References 38 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…) and non‐small cell lung cancer cells (Watarai et al . ). In addition, GSK‐J4 inhibits paediatric brainstem glioma by targeting the oncogenic mutation in histone variant H3.3 (Hashizume et al .…”

Section: Discussionmentioning

confidence: 97%

“…GSK-J4 has been shown to inhibit cancers and inflammatory diseases. It inhibits histone demethylase activity, which is essential for the growth of T-cell acute lymphoblastic leukaemia (Ntziachristos et al 2014) and non-small cell lung cancer cells (Watarai et al 2016). In addition, GSK-J4 inhibits paediatric brainstem glioma by targeting the oncogenic mutation in histone variant H3.3 (Hashizume et al 2014).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Hong

Huang

Xiu-qin

et al. 2018

The Journal of Physiology

View full text Add to dashboard Cite

Key points Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Abstract Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Hong

Huang

Xiu-qin

et al. 2018

The Journal of Physiology

View full text Add to dashboard Cite

show abstract

“…Although GSK-J4 can also be used as a UTX inhibitor of H3K27 demethylation for therapy against T-cell acute lymphoblastic leukemia [ 25 ], however, GSK-J4 is used as a JMJD3 inhibitor in most cases [ 26 ]. In addition to pediatric glioma [ 10 , 11 ], GSK-J4 has also showed significant anti-tumor effect on many cancers, such as acute lymphoblastic leukaemia, ovarian cancer and non-small cell lung cancer [ 27 – 29 ].…”

Section: Discussionmentioning

confidence: 99%

The pharmacological role of histone demethylase JMJD3 inhibitor GSK-J4 on glioma cells

Sui

et al. 2017

Oncotarget

View full text Add to dashboard Cite

Glioma is regarded as the most prevalent malignant carcinoma of the central nervous system, and lack of effective treatment. Thus, the development of new therapeutic strategies targeting glioma is of significant clinical importance. In the present study, histone H3K27 demethylase jumonji domain-containing protein 3 (JMJD3) was investigated as target for glioma treatment. The mRNA of JMJD3 was overexpressed in glioblastoma tissues compared to normal brain tissues (P<0.05). The content of JMJD3 was also higher in glioma cells than in human brain microvascular endothelial cell (hCMEC), and the corresponding level of H3K27me3 was decreased (P<0.05). The treatment with JMJD3 specific inhibitor GSK-J4 can increase the content of H3K27me3 in glioma cells, which means the activity of JMJD3 was inhibited. GSK-J4 can inhibit glioma cell proliferation in a concentration dependent and time-dependent manner (P<0.05). GSK-J4 also induced glioma cell apoptosis and inhibited cell migration (P<0.05). But there was no obvious effect of GSK-J4 on hCMEC cells. All together, these data suggest that GSK-J4 has important potential in the gliomas treatment.

show abstract

“…This effect was potentiated in combination with both lomustine and etoposide. In agreement to our findings of H3K27 wild‐type tumor cell sensitivity to GSK‐J4, ovarian cancer and non‐small‐cell lung cancer are killed by GSK‐J4, irrespective of H3K27 mutational status (Sakaki et al ., ; Watarai et al ., ). Heinemann et al .…”

Section: Discussionmentioning

confidence: 97%

Targeting glioma stem‐like cell survival and chemoresistance through inhibition of lysine‐specific histone demethylase KDM2B

et al. 2018

View full text Add to dashboard Cite

Glioblastoma (GBM) ranks among the most lethal cancers, with current therapies offering only palliation. Inter‐ and intrapatient heterogeneity is a hallmark of GBM, with epigenetically distinct cancer stem‐like cells (CSCs) at the apex. Targeting GSCs remains a challenging task because of their unique biology, resemblance to normal neural stem/progenitor cells, and resistance to standard cytotoxic therapy. Here, we find that the chromatin regulator, JmjC domain histone H3K36me2/me1 demethylase KDM2B, is highly expressed in glioblastoma surgical specimens compared to normal brain. Targeting KDM2B function genetically or pharmacologically impaired the survival of patient‐derived primary glioblastoma cells through the induction of DNA damage and apoptosis, sensitizing them to chemotherapy. KDM2B loss decreased the GSC pool, which was potentiated by coadministration of chemotherapy. Collectively, our results demonstrate KDM2B is crucial for glioblastoma maintenance, with inhibition causing loss of GSC survival, genomic stability, and chemoresistance.

show abstract

Impact of H3K27 Demethylase Inhibitor GSKJ4 on NSCLC Cells Alone and in Combination with Metformin

Abstract: GSKJ4, being a promising anticancer agent for NSCLC, may be effective against a wider spectrum of cancers than previously thought.

Cited by 28 publications

References 38 publications

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

Histone demethylase UTX is a therapeutic target for diabetic kidney disease

The pharmacological role of histone demethylase JMJD3 inhibitor GSK-J4 on glioma cells

Targeting glioma stem‐like cell survival and chemoresistance through inhibition of lysine‐specific histone demethylase KDM2B

Contact Info

Product

Resources

About