PXD013139

PXD013139 is an original dataset announced via ProteomeXchange.

Title	Targeting the E2F1/GAS5/p53 Axis as a Potential Therapeutic Strategy for Gefitinib-Resistant Lung Cancer
Description	Lung cancer is one of the most common and fatal cancer worldwide. There are two major types of lung cancer, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Recently, gefitinib, a small molecule, which target tyrosine kinase, has been regarded as the first-line treatment in NSCLC patients. However, several patients have been observed tumor recurrence and eventually developed progressive outcomes after target therapy. Thus, an effective therapeutic approach need to be explored. Here, we found that ectopically expressed ATP synthase on plasma membrane exhibited gefitinib-resistance properties in lung cancer cell lines. Furthermore, we unraveled that citreoviridin, an ectopic ATP synthase inhibitor, suppressed the abilities of both proliferation and colony formation in lung cancer cell lines. To elucidate the comprehensive mechanism regulated by citreoviridin, we performed microarray analysis. The results indicated that not only mRNAs but also long non-coding RNAs (lncRNAs) are involved in citreoviridin-treated cell death. One of the well-known lncRNAs, growth arrest-specific transcript (GAS5), was robustly upregulated after citreoviridin treatment. In order to investigate the upstream modulator of GAS5, we utilized chromatin immunoprecipitation (ChIP) assay and revealed that E2F transcription factor 1 (E2F1) could bind to the promoter of GAS5. Consistently, both microarray and qPCR data showed the expression level of E2F1 was negatively correlated to GAS5 after citreoviridin treatment. The evidence suggests that E2F1 might be a potential repressor of GAS5. Furthermore, combining microarray and Gene Set Enrichment Analysis (GSEA) analysis as well as qPCR demonstrated that p53 pathway was activated. To further realize the GAS5-p53 regulating network, RNA-protein pull-down assay followed by LC-MS/MS will be utilized to dissect the GAS5-interacting proteomic profiling.From the results, we identified 107 GAS5-interacting proteins in common from A549 and H1975 cell lines. Our proteomics experiments identified topoisomerase 2-alpha (TOP2A) as the key protein involved in the citreoviridin-regulated gefitinib-resistance pathway, therefore, we picked out TOP2A for further study. Additionally, we further validated the interaction between TOP2A and GAS5 by western blot and RNA immunoprecipitation (RIP). Taken together, this study suggests targeting E2F1/GAS5/p53 axis is a potential therapeutic strategy for gefitinib-resistant lung cancer.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:10:56.842.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yi-Wen Chang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap XL

Revision	Datetime	Status	ChangeLog Entry
0	2019-03-19 02:51:52	ID requested
1	2020-08-16 23:58:12	announced
⏵ 2	2024-10-22 05:10:57	announced	2024-10-22: Updated project metadata.

10.1074/mcp.ra120.002219;

Chang YW, Hsu CL, Tang CW, Chen XJ, Huang HC, Juan HF, Multiomics Reveals Ectopic ATP Synthase Blockade Induces Cancer Cell Death via a lncRNA-mediated Phospho-signaling Network. Mol Cell Proteomics, 19(11):1805-1825(2020) [pubmed]

submitter keyword: lung cancer, ectopic ATP synthase, LncRNA-interactomics, gefitinib resistance

Hsueh-Fen Juan
contact affiliation	Department of Life Science, National Taiwan University
contact email	yukijuan@ntu.edu.tw
lab head
Yi-Wen Chang
contact affiliation	Department of Life Science, National Taiwan University
contact email	iwen90322@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013139
     1. Label: PRIDE project
     2. Name: Targeting the E2F1/GAS5/p53 Axis as a Potential Therapeutic Strategy for Gefitinib-Resistant Lung Cancer