TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy

Song, Tanjing; Lv, Suli; Ma, Xianyun; Zhao, Xuefeng; Li, Fan; Zou, Qingli; Li, Neng; Yan, Yingying; Zhang, Wen; Sun, Lidong

doi:10.1016/j.jbc.2023.104621

Cited by 12 publications

(10 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These novel findings differ from TRIM28's published roles 42,98 that include context-specific oncogene [99][100][101][102][103][104][105][106][107][108][109] and tumor suppressor [110][111][112][113][114][115] functions, roles that were primarily determined from complete (homozygous) knockouts. In contrast to homozygous knockout models, the Trim28 +/D9 haplo-insufficient mouse exhibits near normal levels of TRIM28 throughout the body 44 .…”

Section: Role Of Epigenetics In the Developmental Origin Of Cancercontrasting

confidence: 74%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

View full text Add to dashboard Cite

DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility ′states′ in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.

show abstract

Section: Role Of Epigenetics In the Developmental Origin Of Cancercontrasting

confidence: 74%

Developmental priming of cancer susceptibility

Panzeri,

Fagnocchi,

Apostle

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Our findings indicate that KAP1 serves as a novel prognostic marker for NB. KAP1 has been demonstrated to function in the regulation of gene expression [ 41 ], DNA damage [ 42 , 43 ], protein ubiquitination [ 44 ], epithelial to mesenchymal transition [ 45 ], stem cell pluripotency [ 46 ], autophagy [ 47 ], and genome stability [ 19 , 20 ]. To date, however, its relevance in cancer remains elusive.…”

Section: Discussionmentioning

confidence: 99%

KAP1 stabilizes MYCN mRNA and promotes neuroblastoma tumorigenicity by protecting the RNA m6A reader YTHDC1 protein degradation

Yang,

Zhang,

Chen

et al. 2024

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Neuroblastoma (NB) patients with amplified MYCN often face a grim prognosis and are resistant to existing therapies, yet MYCN protein is considered undruggable. KAP1 (also named TRIM28) plays a crucial role in multiple biological activities. This study aimed to investigate the relationship between KAP1 and MYCN in NB. Methods Transcriptome analyses and luciferase reporter assay identified that KAP1 was a downstream target of MYCN. The effects of KAP1 on cancer cell proliferation and colony formation were explored using the loss-of-function assays in vitro and in vivo. RNA stability detection was used to examine the influence of KAP1 on MYCN expression. The mechanisms of KAP1 to maintain MYCN mRNA stabilization were mainly investigated by mass spectrum, immunoprecipitation, RIP-qPCR, and western blotting. In addition, a xenograft mouse model was used to reveal the antitumor effect of STM2457 on NB. Results Here we identified KAP1 as a critical regulator of MYCN mRNA stability by protecting the RNA N6-methyladenosine (m6A) reader YTHDC1 protein degradation. KAP1 was highly expressed in clinical MYCN-amplified NB and was upregulated by MYCN. Reciprocally, KAP1 knockdown reduced MYCN mRNA stability and inhibited MYCN-amplified NB progression. Mechanistically, KAP1 regulated the stability of MYCN mRNA in an m6A-dependent manner. KAP1 formed a complex with YTHDC1 and RNA m6A writer METTL3 to regulate m6A-modified MYCN mRNA stability. KAP1 depletion decreased YTHDC1 protein stability and promoted MYCN mRNA degradation. Inhibiting MYCN mRNA m6A modification synergized with chemotherapy to restrain tumor progression in MYCN-amplified NB. Conclusions Our research demonstrates that KAP1, transcriptionally activated by MYCN, forms a complex with YTHDC1 and METTL3, which in turn maintain the stabilization of MYCN mRNA in an m6A-dependent manner. Targeting m6A modification by STM2457, a small-molecule inhibitor of METTL3, could downregulate MYCN expression and attenuate tumor proliferation. This finding provides a new alternative putative therapeutic strategy for MYCN-amplified NB.

show abstract

“…GSEA analysis was performed as we previously described ( 90 ). RNA-Seq data for prostate cancer samples in The Cancer Genome Atlas (TCGA) program was downloaded from " https://gdc.cancer.gov/ " in the form of STAR counts.…”

Section: Methodsmentioning

confidence: 99%

YTHDF2 protein stabilization by the deubiquitinase OTUB1 promotes prostate cancer cell proliferation via PRSS8 mRNA degradation

Zhao,

Lv,

et al. 2024

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy

Cited by 12 publications

References 54 publications

Developmental priming of cancer susceptibility

Developmental priming of cancer susceptibility

KAP1 stabilizes MYCN mRNA and promotes neuroblastoma tumorigenicity by protecting the RNA m6A reader YTHDC1 protein degradation

YTHDF2 protein stabilization by the deubiquitinase OTUB1 promotes prostate cancer cell proliferation via PRSS8 mRNA degradation

Contact Info

Product

Resources

About