PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth

Cai, Weijia; Su, Liya; Liao, Lili; Liu, Zongzhi Z.; Langbein, Lauren; Dulaimi, Essel; Testa, Joseph R.; Uzzo, Robert G.; Zhong, Zhijiu; Jiang, Wei; Yan, Qin; Zhang, Qing; Yang, Haifeng

doi:10.1038/s41467-019-13608-1

Cited by 60 publications

(49 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P53 research has caught much attention in oncology, including kidney cancer. Although VHL is the most critical mutation in kidney cancer, p53 still has a vital role in the tumorigenesis of kidney cancer 37 . Some studies indicate that p53 is highly expressed in kidney cancer tissues, indicating that p53 may have a cancer-promoting effect on kidney cancer 11,38 .…”

Section: Discussionmentioning

confidence: 99%

Cell-cycle arrest and senescence in TP53-wild type renal carcinoma by enhancer RNA-P53-bound enhancer regions 2 (p53BER2) in a p53-dependent pathway

et al. 2021

View full text Add to dashboard Cite

TP53 is a classic tumor suppressor, but its role in kidney cancer remains unclear. In our study, we tried to explain the role of p53 in kidney cancer through the p53-related enhancer RNA pathway. Functional experiments were used to explore whether P53-bound enhancer regions 2 (p53BER2) has a role in the cell cycle and senescence response of TP53-wild type (WT) renal cancer cells in vitro or vivo. RNA-sequencing was used to identify the potential target of p53BER2. The results showed that the expression level of P53BER2 was downregulated in renal cancer tissues and cell lines, further dual-luciferase experiments and APR-256-reactivated experiments showed p53BER2 expresses in a p53-dependent way. Moreover, knockdown p53BER2 could reverse nutlin-3-induced cytotoxic effect in TP53-WT cell lines. Further exploration showed the downregulation of p53BER2 could reverse nutlin-3-induced G1-arrest and senescence in TP53-WT cell lines. What is more, the knockdown of p53BER2 showed resistance to nutlin-3 treatment in vivo. Additionally, we found BRCA2 could be regulated by p53BER2 in vitro and vivo; further experiment showed p53BER2 could induce cell-cycle arrest and DNA repair by mediating BRCA2. In summary, the p53-associated enhancer RNA-p53BER2 mediates the cell cycle and senescence of p53 in TP53-WT renal cancer cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Cell-cycle arrest and senescence in TP53-wild type renal carcinoma by enhancer RNA-P53-bound enhancer regions 2 (p53BER2) in a p53-dependent pathway

et al. 2021

View full text Add to dashboard Cite

show abstract

“…These findings indicate that ccRCC may be unique compared with other cancers with respect to TME modulation and immunotherapy response, and that immunosuppression from PBRM1 loss is unique to ccRCC. PBRM1 has been shown to have pleiotropic effects at a molecular level, including the recognition of acetylated histones and p53, while different bromodomains can either enhance or attenuate nucleosome interaction 55,56 . Tissue specific cells are programmed to express a set of genes unique to that cell type, and each tumor type has additional canonical mutations specific to that tumor.…”

Section: Discussionmentioning

confidence: 99%

PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma

et al. 2020

View full text Add to dashboard Cite

A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.

show abstract

“…We observed that magnolol and MM1 enhanced p21 expression by inducing histone acetylation, thereby inhibiting cyclin D1 and CDK4 activities, as well as cell cycle progression. Additionally, magnolol and MM1 also induce p53 protein acetylation, which not only enhances its stability but also improves its ability to bind to the target gene promoter, thereby upregulating the expression of downstream tumor-suppressor genes such as p21 and BAX (58). These results indicated that magnolol and MM1 could regulate p21 expression via both direct and indirect pathways and consequently inhibit tumor growth.…”

Section: Discussionmentioning

confidence: 94%

2-O-Methylmagnolol, a Magnolol Derivative, Suppresses Hepatocellular Carcinoma Progression via Inhibiting Class I Histone Deacetylase Expression

et al. 2020

View full text Add to dashboard Cite

Magnolia officinalis is widely used in Southeast Asian countries for the treatment of fever, headache, diarrhea, and stroke. Magnolol is a phenolic compound extracted from M. officinalis, with proven antibacterial, antioxidant, anti-inflammatory, and anticancer activities. In this study, we modified magnolol to synthesize a methoxylated derivative, 2-O-methylmagnolol (MM1), and investigated the use of MM1, and magnolol in the treatment of liver cancer. We found that both magnolol and MM1 exhibited inhibitory effects on the growth, migration, and invasion of hepatocellular carcinoma (HCC) cell lines and halted the cell cycle at the G1 phase. MM1 also demonstrated a substantially better tumor-suppressive effect than magnolol. Further analysis suggested that by inhibiting class I histone deacetylase expression in HCC cell lines, magnolol and MM1 induced p21 expression and p53 activation, thereby causing cell cycle arrest and inhibiting HCC cell growth, migration, and invasion. Subsequently, we verified the significant tumor-suppressive effects of magnolol and MM1 in an animal model. Collectively, these findings demonstrate the anti-HCC activities of magnolol and MM1 and their potential for clinical use.

show abstract

PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth

Cited by 60 publications

References 48 publications

Cell-cycle arrest and senescence in TP53-wild type renal carcinoma by enhancer RNA-P53-bound enhancer regions 2 (p53BER2) in a p53-dependent pathway

Cell-cycle arrest and senescence in TP53-wild type renal carcinoma by enhancer RNA-P53-bound enhancer regions 2 (p53BER2) in a p53-dependent pathway

PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma

2-O-Methylmagnolol, a Magnolol Derivative, Suppresses Hepatocellular Carcinoma Progression via Inhibiting Class I Histone Deacetylase Expression

Contact Info

Product

Resources

About