Apcin inhibits the growth and invasion of glioblastoma cells and improves glioma sensitivity to temozolomide

Ding, Yiming; Zhang, Chuanbao; He, Lei; Song, Xinyu; Zheng, Chengjun; Pan, Yuchu; Yu, Shuqing

doi:10.1080/21655979.2021.2003927

“…The accumulation of evidence has demonstrated that CDC20 is dramatically elevated in human malignancies (including pancreatic cancer, breast cancer, and lung cancer), and CDC20 contributes to the malignant progression of cancer by degradation of its downstream target genes (such as CDKN1A (P21), Cyclin B1, and Bim) through ubiquitination, making it a promising target for cancer treatment [24]. In glioma, CDC20 has been identified as an oncogenic factor mediating tumor cell growth, invasion, and chemosensitivity [25]. Targeting CDC20 inhibits the malignant progression of glioma and CDC20 is considered an attractive target for therapeutic intervention [26,27].…”

Section: Introductionmentioning

confidence: 99%

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

Wang

¹

,

Xiao

²

,

Wu

³

et al. 2023

View full text Add to dashboard Cite

PRMT6, a type I arginine methyltransferase, di-methylates the arginine residues of both histones and non-histones asymmetrically. Increasing evidence indicates that PRMT6 plays a tumor mediator involved in human malignancies. Here, we aim to uncover the essential role and underlying mechanisms of PRMT6 in promoting glioblastoma (GBM) proliferation. Investigation of PRMT6 expression in glioma tissues demonstrated that PRMT6 is overexpressed, and elevated expression of PRMT6 is negatively correlated with poor prognosis in glioma/GBM patients. Silencing PRMT6 inhibited GBM cell proliferation and induced cell cycle arrest at the G0/G1 phase, while overexpressing PRMT6 had opposite results. Further, we found that PRMT6 attenuates the protein stability of CDKN1B by promoting its degradation. Subsequent mechanistic investigations showed that PRMT6 maintains the transcription of CDC20 by activating histone methylation mark (H3R2me2a), and CDC20 interacts with and destabilizes CDKN1B. Rescue experimental results confirmed that PRMT6 promotes the ubiquitinated degradation of CDKN1B and cell proliferation via CDC20. We also verified that the PRMT6 inhibitor (EPZ020411) could attenuate the proliferative effect of GBM cells. Our findings illustrate that PRMT6, an epigenetic mediator, promotes CDC20 transcription via H3R2me2a to mediate the degradation of CDKN1B to facilitate GBM progression. Targeting PRMT6-CDC20-CDKN1B axis might be a promising therapeutic strategy for GBM.

show abstract

“…Inhibition of CDC20 has been demonstrated in multiple cancer cell models including PCa by the compound Apcin (175)(176)(177). Mechanistically, it acts as an APC-CDC20 E3 ligase inhibitor, thus interfering with CDC20 binding to its substrates, causing a blockade of mitotic exit and consequently apoptosis.…”

Section: Cdc20mentioning

confidence: 99%

A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer

Miller

¹

,

Henry

²

,

Maylin

³

et al. 2023

Front. Oncol.

9

0

View full text Add to dashboard Cite

Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.

show abstract

“…The accumulation of evidence has demonstrated that CDC20 is dramatically elevated in human malignancies (including pancreatic cancer, breast cancer, and lung cancer), and CDC20 contributes to the malignant progression of cancer by degradation of its downstream target genes (such as CDKN1A, Cyclin B1, and Bim) through ubiquitination, making it a promising target for cancer treatment [24]. In glioma, CDC20 has been identi ed as an oncogenic factor mediating tumor cell growth, invasion, and chemosensitivity [25]. Targeting CDC20 inhibits the malignant progression of glioma and CDC20 is considered an attractive target for therapeutic intervention [26,27].…”

Section: Introductionmentioning

confidence: 99%

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

Wang¹,

Wang²,

Xiao³

et al. 2022

Preprint

0

View full text Add to dashboard Cite

PRMT6, a type I arginine methyltransferase, di-methylates the arginine residues of both histones and non-histones asymmetrically. Increasing evidence indicates that PRMT6 plays a tumor mediator involved in human malignancies. Here, we aim to uncover the essential role and underlying mechanisms of PRMT6 in promoting glioblastoma (GBM) proliferation. Investigation of PRMT6 expression in glioma tissues demonstrated that PRMT6 is overexpressed, and elevated expression of PRMT6 is negatively correlated with poor prognosis in glioma/GBM patients. Silencing PRMT6 inhibited GBM cell proliferation and induced cell cycle arrest at the G0/G1 phase, while overexpressing PRMT6 had opposite results. Further, we found that PRMT6 attenuates the protein stability of CDKN1B by promoting its degradation. Subsequent mechanistic investigations showed that PRMT6 maintains the transcription of CDC20 by activating histone methylation mark (H3R2me2a), and CDC20 interacts with and destabilizes CDKN1B. Rescue experimental results confirmed that PRMT6 promotes the ubiquitinated degradation of CDKN1B and cell proliferation via CDC20. We also verified that the PRMT6 inhibitor (EPZ020411) could attenuate the proliferative effect of GBM cells. Our findings illustrate that PRMT6, an epigenetic mediator, promotes CDC20 transcription via H3R2me2a to mediate the degradation of CDKN1B to facilitate GBM progression. Targeting PRMT6-CDC20-CDKN1B axis might be a promising therapeutic strategy for GBM.

show abstract

Apcin inhibits the growth and invasion of glioblastoma cells and improves glioma sensitivity to temozolomide

Cited by 11 publications

References 32 publications

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B

Contact Info

Product

Resources

About