Publications by authors named "Simranjit X Singh"

5 Publications

  • Page 1 of 1

A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis.

Cell Rep 2019 09;28(12):3199-3211.e5

The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:

H2AX safeguards genomic stability in a dose-dependent manner; however, mechanisms governing its proteostasis are poorly understood. Here, we identify a PRMT5-RNF168-SMURF2 cascade that regulates H2AX proteostasis. We show that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for DNA damage response (DDR). Suppression of PRMT5 occurs in methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells and attenuates the expression of RNF168, leading to destabilization of H2AX by E3 ubiquitin ligase SMURF2. RNF168 and SMURF2 serve as a stabilizer and destabilizer of H2AX, respectively, via their dynamic interactions with H2AX. In supporting an important role of this signaling cascade in regulating H2AX, MTAP-deficient glioblastoma cells display higher levels of DNA damage spontaneously or in response to genotoxic agents. These findings reveal a regulatory mechanism of H2AX proteostasis and define a signaling cascade that is essential to DDR and that is disrupted by the loss of a metabolic enzyme in tumor cells.
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http://dx.doi.org/10.1016/j.celrep.2019.08.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204040PMC
September 2019

MTAP Loss Promotes Stemness in Glioblastoma and Confers Unique Susceptibility to Purine Starvation.

Cancer Res 2019 07 30;79(13):3383-3394. Epub 2019 Apr 30.

The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.

Homozygous deletion of methylthioadenosine phosphorylase () is one of the most frequent genetic alterations in glioblastoma (GBM), but its pathologic consequences remain unclear. In this study, we report that loss of MTAP results in profound epigenetic reprogramming characterized by hypomethylation of /CD133-associated stem cell regulatory pathways. MTAP deficiency promotes glioma stem-like cell (GSC) formation with increased expression of /CD133 and enhanced tumorigenicity of GBM cells and is associated with poor prognosis in patients with GBM. As a combined consequence of purine production deficiency in -null GBM and the critical dependence of GSCs on purines, the enriched subset of CD133 cells in -null GBM can be effectively depleted by inhibition of purine synthesis. These findings suggest that MTAP loss promotes the pathogenesis of GBM by shaping the epigenetic landscape and stemness of GBM cells while simultaneously providing a unique opportunity for GBM therapeutics. SIGNIFICANCE: This study links the frequently mutated metabolic enzyme MTAP to dysregulated epigenetics and cancer cell stemness and establishes MTAP status as a factor for consideration in characterizing GBM and developing therapeutic strategies.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810595PMC
July 2019

Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis.

Nat Med 2017 Nov 2;23(11):1362-1368. Epub 2017 Oct 2.

Department of Pathology, New York University School of Medicine, New York, New York, USA.

Treating KRAS-mutant lung adenocarcinoma (LUAD) remains a major challenge in cancer treatment given the difficulties associated with directly inhibiting the KRAS oncoprotein. One approach to addressing this challenge is to define mutations that frequently co-occur with those in KRAS, which themselves may lead to therapeutic vulnerabilities in tumors. Approximately 20% of KRAS-mutant LUAD tumors carry loss-of-function mutations in the KEAP1 gene encoding Kelch-like ECH-associated protein 1 (refs. 2, 3, 4), a negative regulator of nuclear factor erythroid 2-like 2 (NFE2L2; hereafter NRF2), which is the master transcriptional regulator of the endogenous antioxidant response. The high frequency of mutations in KEAP1 suggests an important role for the oxidative stress response in lung tumorigenesis. Using a CRISPR-Cas9-based approach in a mouse model of KRAS-driven LUAD, we examined the effects of Keap1 loss in lung cancer progression. We show that loss of Keap1 hyperactivates NRF2 and promotes KRAS-driven LUAD in mice. Through a combination of CRISPR-Cas9-based genetic screening and metabolomic analyses, we show that Keap1- or Nrf2-mutant cancers are dependent on increased glutaminolysis, and this property can be therapeutically exploited through the pharmacological inhibition of glutaminase. Finally, we provide a rationale for stratification of human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to respond to glutaminase inhibition.
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http://dx.doi.org/10.1038/nm.4407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677540PMC
November 2017

Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer.

Elife 2017 10 2;6. Epub 2017 Oct 2.

Department of Pathology, New York University School of Medicine, New York, United States.

During tumorigenesis, the high metabolic demand of cancer cells results in increased production of reactive oxygen species. To maintain oxidative homeostasis, tumor cells increase their antioxidant production through hyperactivation of the NRF2 pathway, which promotes tumor cell growth. Despite the extensive characterization of NRF2-driven metabolic rewiring, little is known about the metabolic liabilities generated by this reprogramming. Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by x antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. Cancers with genetic or pharmacological activation of the NRF2 antioxidant pathway have a metabolic imbalance between supporting increased antioxidant capacity over central carbon metabolism, which can be therapeutically exploited.
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http://dx.doi.org/10.7554/eLife.28083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624783PMC
October 2017

Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events.

Nat Commun 2016 10 25;7:13197. Epub 2016 Oct 25.

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden.

Thousands of long non-coding RNAs (lncRNAs) lie interspersed with coding genes across the genome, and a small subset has been implicated as downstream effectors in oncogenic pathways. Here we make use of transcriptome and exome sequencing data from thousands of tumours across 19 cancer types, to identify lncRNAs that are induced or repressed in relation to somatic mutations in key oncogenic driver genes. Our screen confirms known coding and non-coding effectors and also associates many new lncRNAs to relevant pathways. The associations are often highly reproducible across cancer types, and while many lncRNAs are co-expressed with their protein-coding hosts or neighbours, some are intergenic and independent. We highlight lncRNAs with possible functions downstream of the tumour suppressor TP53 and the master antioxidant transcription factor NFE2L2. Our study provides a comprehensive overview of lncRNA transcriptional alterations in relation to key driver mutational events in human cancers.
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http://dx.doi.org/10.1038/ncomms13197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093340PMC
October 2016