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| Status |
Public on Aug 02, 2022 |
| Title |
Transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor–resistant pancreatic ductal adenocarcinoma |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Metabolic reprogramming, due in part to the overexpression of metabolic enzymes, is a key hallmark of cancer cells. Lactate dehydrogenase (LDHA), a metabolic enzyme that catalyzes the interconversion of lactate and pyruvate, is overexpressed in a wide variety of cancer types, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, the genetic or pharmacological inhibition of LDHA suppresses cancer growth, demonstrating a cancer-promoting role for this enzyme. Therefore, several pharmacological LDHA inhibitors are being developed and tested as potential anti-cancer therapeutic agents. Because cancer cells are known to rapidly adapt and become resistant to anti-cancer therapies, in this study, we modeled the adaptation of cancer cells to LDHA inhibition. Using PDAC as a model system, we studied the molecular aspects of cells resistant to the competitive LDHA inhibitor sodium oxamate. We performed unbiased RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and metabolomics analyses of parental and oxamate-resistant PDAC cells treated with and without oxamate to identify the transcriptional, chromatin, and metabolic landscapes of these cells. We found that oxamate-resistant PDAC cells were significantly different from parental cells at the levels of mRNA expression, chromatin accessibility, and metabolites. Additionally, an integrative analysis combining the RNA-seq and ATAC-seq datasets identified a subset of differentially expressed mRNAs that directly correlated with changes in chromatin accessibility. Finally, functional analysis of differentially expressed metabolic genes in parental and oxamate-resistant PDAC cells treated with and without oxamate, together with an integrative analysis of RNA-seq and metabolomics data, revealed changes in metabolic enzymes that might explain the changes in metabolite levels observed in these cells. Collectively, these studies identify the transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor resistance in PDAC cells. Future functional studies related to these changes remain necessary to reveal the direct roles played by these changes in the development of LDHA inhibitor resistance and uncover approaches for more effective use of LDHA inhibitors in cancer therapy.
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| Overall design |
ATAC-seq analysis was done in Miapaca2 parental and LDHA inhibitor resistant cells.
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| Contributor(s) |
Rawat V, Malvi P, Gupta R, Wajapeyee N |
| Citation(s) |
35982980 |
| Submission date |
Jan 17, 2021 |
| Last update date |
Aug 26, 2022 |
| Contact name |
Narendra Wajapeyee |
| E-mail(s) |
nwajapey@uab.edu
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| Phone |
205-934-5331
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| Organization name |
University of Alabama at Birmingham
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| Department |
Department of Biochemistry and Molecular Genetics
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| Street address |
720 20th Street South, Kaul 540A
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| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35233 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (12)
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| GSM5024015 |
Parental-Untreated replicate 1 (ATAC-seq) |
| GSM5024016 |
Parental-Untreated replicate 2 (ATAC-seq) |
| GSM5024017 |
Parental-Untreated replicate 3 (ATAC-seq) |
| GSM5024018 |
Parental-treated-replicate 1 (ATAC-seq) |
| GSM5024019 |
Parental-treated-replicate 2 (ATAC-seq) |
| GSM5024020 |
Parental-treated-replicate 3 (ATAC-seq) |
| GSM5024021 |
Resistant-untreated replicate 1 (ATAC-seq) |
| GSM5024022 |
Resistant-untreated replicate 2 (ATAC-seq) |
| GSM5024023 |
Resistant-untreated replicate 3 (ATAC-seq) |
| GSM5024024 |
Resistant-treated replicate 1 (ATAC-seq) |
| GSM5024025 |
Resistant-treated replicate 2 (ATAC-seq) |
| GSM5024026 |
Resistant-treated replicate 3 (ATAC-seq) |
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| Relations |
| BioProject |
PRJNA692718 |
| SRA |
SRP302098 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE164974_RAW.tar |
16.2 Mb |
(http)(custom) |
TAR (of BROADPEAK) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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