Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells

Shi, Lei; Tan, Xiaochao; Liu, Xin; Yu, Jian; Bota-Rabassedas, Neus; Niu, Yichi; Luo, Jiayi; Xi, Yuanxin; Zong, Chenghang; Creighton, Chad J.; Glenn, Jeffrey S.; Wang, Jing; Kurie, Jonathan M.

doi:10.1073/pnas.2023537118

Cited by 15 publications

(16 citation statements)

References 24 publications

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“…Reminiscently, an increase in the number and size of LD had already been reported in mrx mutants, deficient in DSB sensing and repair 62 . DDR attenuation could also occur, as recently reported, by an exacerbated synthesis of PI(4)P, to which adenocarcinoma cells are addict 63 . In support, recent findings highlight the potential of targeting the metabolism of cholesterol for modulating the DDR in gallbladder cancer 64 .…”

Section: Discussionsupporting

confidence: 57%

A Sterol-PI(4)P exchanger controls the Tel1/ATM axis of the DNA Damage Response

Ovejero

Kumanski

Soulet

et al. 2022

Preprint

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Upon DNA damage, cells activate the DNA Damage Response (DDR) to coordinate proliferation and DNA repair. Dietary, metabolic, and environmental inputs are emerging as modulators of how DNA surveillance and repair take place. Lipids hold potential to convey these cues, although little is known about how. We observed that lipid droplet (LD) number specifically increased in response to DNA breaks. We show that the selective storage of sterols into these LD concomitantly stabilizes phosphatidyl-4-inositol (PI(4)P) at the Golgi, where it binds the DDR kinase ATM. In turn, this titration attenuates the initial nuclear ATM-driven response to DNA breaks, thus allowing processive repair. Further, manipulating this loop impacts the kinetics of DNA damage signaling and repair in a predictable manner. Thus, our findings have major implications for tackling genetic instability pathologies through dietary and pharmacological interventions.

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Section: Discussionsupporting

confidence: 57%

A Sterol-PI(4)P exchanger controls the Tel1/ATM axis of the DNA Damage Response

Ovejero

Kumanski

Soulet

et al. 2022

Preprint

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“…Furthermore, amplification of the interleukin-2 enhancer binding factor 2 (ILF2) gene in the 1q21.3 region is closely related to the invasiveness of skin melanoma ( 21 ), and amplification of the Jun Proto-Oncogene (JUN) gene in the 1q21.3 region is closely related to the occurrence and development of thyroid cancer ( 22 ). Moreover, a study has also shown that pi4kii β amplification in the 1q21.3 region is closely associated with LUAD ( 9 ). In this study, the copy number coefficient of variation (CV) of the genes in the 1q21.3 region was screened, and the statistical analysis indicated that ENFA3 was an LUAD driver gene.…”

Section: Discussionmentioning

confidence: 99%

“…The amplification of some regions of chromosomes is the main cause of an increase in copy number. For instance, amplification of the 9p24.1 region in triple-negative breast cancer significantly increases the copy number of immune-related genes, thereby promoting disease progression in patients ( 9 ). Also, amplification of the 1q21 region in patients with multiple myeloma is closely related to the clinical stage of the disease.…”

Section: Introductionmentioning

confidence: 99%

The 1q21.3 region driver gene EFNA3 promotes disease progression via inhibition of lung adenocarcinoma cell apoptosis

Dong¹,

Wu²,

Guo³

et al. 2022

Transl Cancer Res TCR

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Background Lung adenocarcinoma (LUAD) is the leading cause of cancer deaths in the world. Therefore, it is necessary to explore the underlying mechanism of EFNA3 (a 1q21.3 region driver gene) in the progression of LUAD cells. Methods Differentially-expressed genes (DEGs) in LUAD tissues were screened based on The Cancer Genome Atlas (TCGA) database. The gene copy number variations in the 1q21.3 region were clarified by copy number variation analysis. Genes associated with overall survival (OS) were identified by Kaplan-Meier (KM) analysis. The intersection of the genes was used to obtain the driver genes. LUAD patients were grouped with driver gene expression, and the DEGs were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to identify the enrichment pathways of the driver genes. EFNA3 was knocked down using lentiviral infection in A549 and PC9 cell lines. The efficiencies of lentiviral infection were confirmed by RT-PCR (reverse transcription polymerase chain reaction). After EFNA3 knockdown, changes in cell viability were confirmed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, changes in cell proliferation and apoptosis were confirmed by enzyme-linked immunosorbent assay (ELISA), while changes in the expression of apoptosis-related proteins ( Bax and caspase 3 ) were confirmed by RT-PCR and western blot. Results A total of 483 LUAD samples and 59 normal control samples were obtained from TCGA database, and 640 upregulated genes were identified. 154 genes with a coefficient of copy number variations greater than 10% in the 1q23.1 region and 1,247 genes that were significantly associated with patient OS were selected. The intersection results indicated that EFNA3 might be a driver gene of LUAD. KEGG enrichment analysis indicated that the DEGs were mainly enriched in apoptosis-related pathways. Cell experiments showed that after lentiviral knockdown of EFNA3 , EFNA3 messenger RNA (mRNA) and protein expression was significantly reduced (P<0.05), cell viability was markedly reduced (P<0.05), LUAD cell apoptosis increased notably (P<0.05), and LUAD cell proliferation decreased significantly (P<0.05). After EFNA3 knockdown, the expression of apoptosis-related proteins ( Bax and caspase3 ) and mRNA in LUAD cells increased markedly (P<0.05). Conclusions As a driver gene in the progression of LUAD, EFNA3 mainly affects the progression of LUAD by regulating LUAD cell apoptosis.

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“…There are some preclinical data that highlight the potential for targeting PI4KA and PI4KB in cancer [185][186][187][188] . PI4KA generates the PI4P pool at the plasma membrane, which is phosphorylated into PI(4,5)P 2 , which can be further phosphorylated into the pro-growth signal PIP 3 .…”

Section: Pi4ka and Pi4kb Inhibition In Cancermentioning

confidence: 99%

Beyond PI3Ks: targeting phosphoinositide kinases in disease

Burke

Triscott

Emerling

et al. 2022

Nat Rev Drug Discov

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Lipid phosphoinositides are master regulators of almost all aspects of a cell's life and death and are generated by the tightly regulated activity of phosphoinositide kinases. Although extensive efforts have focused on drugging class I phosphoinositide 3-kinases (PI3Ks), recent years have revealed opportunities for targeting almost all phosphoinositide kinases in human diseases, including cancer, immunodeficiencies, viral infection and neurodegenerative disease. This has led to widespread efforts in the clinical development of potent and selective inhibitors of phosphoinositide kinases. This Review summarizes our current understanding of the molecular basis for the involvement of phosphoinositide kinases in disease and assesses the preclinical and clinical development of phosphoinositide kinase inhibitors.

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Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells

Cited by 15 publications

References 24 publications

A Sterol-PI(4)P exchanger controls the Tel1/ATM axis of the DNA Damage Response

A Sterol-PI(4)P exchanger controls the Tel1/ATM axis of the DNA Damage Response

The 1q21.3 region driver gene EFNA3 promotes disease progression via inhibition of lung adenocarcinoma cell apoptosis

Beyond PI3Ks: targeting phosphoinositide kinases in disease

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