3D CRISPR screen in prostate cancer cells reveals PARP inhibitor sensitization through TBL1XR1-SMC3 interaction

Zhang, Huan; Gao, Huanyao; Gu, Yayun; John, August; Wei, Lixuan; Huang, Minhong; Yu, Jia; Adeosun, Adeyemi A; Weinshilboum, Richard M.; Wang, Liewei

doi:10.3389/fonc.2022.999302

Cited by 4 publications

(5 citation statements)

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“…Gastric tissues and cells that were resistant to cisplatin displayed an evident boost in TBL1XR1 expression ( 53 ). CRISPR screen experiments identified TBL1XR1 as a candidate gene associated with PARP inhibitor resistance in prostate cancer cells ( 54 ). A greater sensitivity to the PARP inhibitor olaparib was caused by TBL1XR1 deletion ( 54 ).…”

Section: Oncogenic Functions Of Tbl1xr1 In Cancersmentioning

confidence: 99%

“…CRISPR screen experiments identified TBL1XR1 as a candidate gene associated with PARP inhibitor resistance in prostate cancer cells ( 54 ). A greater sensitivity to the PARP inhibitor olaparib was caused by TBL1XR1 deletion ( 54 ). Additionally, in both 2D and 3D culture, the olaparib-resistant cells with TBL1XR1 deletion were more susceptible to olaparib treatment ( 54 ).…”

Section: Oncogenic Functions Of Tbl1xr1 In Cancersmentioning

confidence: 99%

“…A greater sensitivity to the PARP inhibitor olaparib was caused by TBL1XR1 deletion ( 54 ). Additionally, in both 2D and 3D culture, the olaparib-resistant cells with TBL1XR1 deletion were more susceptible to olaparib treatment ( 54 ). In terms of mechanism in prostate cancer cells, PARP1 plays an important role in the susceptibility of TBL1XR1 deletion cells to PARP inhibitors ( 54 ).…”

Section: Oncogenic Functions Of Tbl1xr1 In Cancersmentioning

confidence: 99%

“…Additionally, in both 2D and 3D culture, the olaparib-resistant cells with TBL1XR1 deletion were more susceptible to olaparib treatment ( 54 ). In terms of mechanism in prostate cancer cells, PARP1 plays an important role in the susceptibility of TBL1XR1 deletion cells to PARP inhibitors ( 54 ). Suppression of the NCoR complex or therapy with the HDAC inhibitor rescues responsiveness to glucocorticoids ( 55 ).…”

Section: Oncogenic Functions Of Tbl1xr1 In Cancersmentioning

confidence: 99%

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Two decades of a protooncogene TBL1XR1: from a transcription modulator to cancer therapeutic target

Du,

Li,

Guo

et al. 2024

Front. Oncol.

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Transducin beta-like 1X-related protein 1 (TBL1XR1) was discovered two decades ago and was implicated as part of the nuclear transcription corepressor complex. Over the past 20 years, the emerging oncogenic function of TBL1XR1 in cancer development has been discovered. Recent studies have highlighted that the genetic aberrations of TBL1XR1 in cancers, especially in hematologic tumors, are closely associated with tumorigenesis. In solid tumors, TBL1XR1 is proposed to be a promising prognostic biomarker due to the correlation between abnormal expression and clinicopathological parameters. Post-transcriptional and post-translational modification are responsible for the expression and function of TBL1XR1 in cancer. TBL1XR1 exerts its functional role in various processes that involves cell cycle and apoptosis, cell proliferation, resistance to chemotherapy and radiotherapy, cell migration and invasion, stemness and angiogenesis. Multitude of cancer-related signaling cascades like Wnt-β-catenin, PI3K/AKT, ERK, VEGF, NF-κB, STAT3 and gonadal hormone signaling pathways are tightly modulated by TBL1XR1. This review provided a comprehensive overview of TBL1XR1 in tumorigenesis, shedding new light on TBL1XR1 as a promising diagnostic biomarker and druggable target in cancer.

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Section: Oncogenic Functions Of Tbl1xr1 In Cancersmentioning

confidence: 99%

Section: Oncogenic Functions Of Tbl1xr1 In Cancersmentioning

confidence: 99%

Section: Oncogenic Functions Of Tbl1xr1 In Cancersmentioning

confidence: 99%

Section: Oncogenic Functions Of Tbl1xr1 In Cancersmentioning

confidence: 99%

See 2 more Smart Citations

Two decades of a protooncogene TBL1XR1: from a transcription modulator to cancer therapeutic target

Du,

Li,

Guo

et al. 2024

Front. Oncol.

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show abstract

“…Zhang et al. screened 3D spheroids from an olaparib-insensitive cell line and demonstrated that deficiency in TBL1XR1, a core component of nuclear receptor corepressor, sensitized prostate cancer cells to PARPi ( 250 ). Screens by Tsujino et al.…”

Section: Parpi Resistance In the Context Of Covalent Parylation And N...mentioning

confidence: 99%

The dynamic process of covalent and non-covalent PARylation in the maintenance of genome integrity: a focus on PARP inhibitors

Beneyton,

Nonfoux,

Gagné

et al. 2023

NAR Cancer

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Poly(ADP-ribosylation) (PARylation) by poly(ADP-ribose) polymerases (PARPs) is a highly regulated process that consists of the covalent addition of polymers of ADP-ribose (PAR) through post-translational modifications of substrate proteins or non-covalent interactions with PAR via PAR binding domains and motifs, thereby reprogramming their functions. This modification is particularly known for its central role in the maintenance of genomic stability. However, how genomic integrity is controlled by an intricate interplay of covalent PARylation and non-covalent PAR binding remains largely unknown. Of importance, PARylation has caught recent attention for providing a mechanistic basis of synthetic lethality involving PARP inhibitors (PARPi), most notably in homologous recombination (HR)-deficient breast and ovarian tumors. The molecular mechanisms responsible for the anti-cancer effect of PARPi are thought to implicate both catalytic inhibition and trapping of PARP enzymes on DNA. However, the relative contribution of each on tumor-specific cytotoxicity is still unclear. It is paramount to understand these PAR-dependent mechanisms, given that resistance to PARPi is a challenge in the clinic. Deciphering the complex interplay between covalent PARylation and non-covalent PAR binding and defining how PARP trapping and non-trapping events contribute to PARPi anti-tumour activity is essential for developing improved therapeutic strategies. With this perspective, we review the current understanding of PARylation biology in the context of the DNA damage response (DDR) and the mechanisms underlying PARPi activity and resistance.

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Mitochondrial stress-induced H4K12 hyperacetylation dysregulates transcription in Parkinson’s disease

Huang,

Jin,

Anantharam

et al. 2024

Front. Cell. Neurosci.

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Aberrant epigenetic modification has been implicated in the pathogenesis of Parkinson’s disease (PD), which is characterized by the irreversible loss of dopaminergic (DAergic) neurons. However, the mechanistic landscape of histone acetylation (ac) in PD has yet to be fully explored. Herein, we mapped the proteomic acetylation profiling changes at core histones H4 and thus identified H4K12ac as a key epigenomic mark in dopaminergic neuronal cells as well as in MitoPark animal model of PD. Notably, the significantly elevated H4K12ac deposition in post-mortem PD brains highlights its clinical relevance to human PD. Increased histone acetyltransferase (HAT) activity and decreased histone deacetylase 2 (HDAC2) and HDAC4 were found in experimental PD cell models, suggesting the HAT/HDAC imbalance associated with mitochondrial stress. Following our delineation of the proteasome dysfunction that possibly contributes to H4K12ac deposition, we characterized the altered transcriptional profile and disease-associated pathways in the MitoPark mouse model of PD. Our study uncovers the axis of mitochondrial impairment-H4K12ac deposition-altered transcription/disease pathways as a neuroepigenetic mechanism underlying PD pathogenesis. These findings provide mechanistic information for the development of potential pharmacoepigenomic translational strategies for PD.

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3D CRISPR screen in prostate cancer cells reveals PARP inhibitor sensitization through TBL1XR1-SMC3 interaction

Cited by 4 publications

References 61 publications

Two decades of a protooncogene TBL1XR1: from a transcription modulator to cancer therapeutic target

Two decades of a protooncogene TBL1XR1: from a transcription modulator to cancer therapeutic target

The dynamic process of covalent and non-covalent PARylation in the maintenance of genome integrity: a focus on PARP inhibitors

Mitochondrial stress-induced H4K12 hyperacetylation dysregulates transcription in Parkinson’s disease

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