A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells

Background Quiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresista...

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Vydané v:	Genome Biology Ročník 21; číslo 1; s. 33
Hlavní autori:	Lee, Sooncheol, Micalizzi, Douglas, Truesdell, Samuel S., Bukhari, Syed I. A., Boukhali, Myriam, Lombardi-Story, Jennifer, Kato, Yasutaka, Choo, Min-Kyung, Dey-Guha, Ipsita, Ji, Fei, Nicholson, Benjamin T., Myers, David T., Lee, Dongjun, Mazzola, Maria A., Raheja, Radhika, Langenbucher, Adam, Haradhvala, Nicholas J., Lawrence, Michael S., Gandhi, Roopali, Tiedje, Christopher, Diaz-Muñoz, Manuel D., Sweetser, David A., Sadreyev, Ruslan, Sykes, David, Haas, Wilhelm, Haber, Daniel A., Maheswaran, Shyamala, Vasudevan, Shobha
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Springer Science and Business Media LLC 10.02.2020 BioMed Central Springer Nature B.V BMC
Predmet:	[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases Animal Genetics and Genomics Animals AU Rich Elements Bioinformatics Biology (General) Biomedical and Life Sciences blood serum Cancer Cell culture Cell Cycle Cells, Cultured Chemoresistance Chemotherapy Drug Resistance, Neoplasm drug therapy Dual Specificity Phosphatase 1 Dual Specificity Phosphatase 1 - genetics Dual Specificity Phosphatase 1 - metabolism Evolutionary Biology Gene expression Gene regulation Genetics genome Hep G2 Cells Human Genetics Human health and pathology Humans Infectious diseases Inflammation Intracellular Signaling Peptides and Proteins Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism K562 Cells Kinases Leukemia Life Sciences MAP kinase MCF-7 Cells MESH: AU Rich Elements MESH: Cells, Cultured MESH: Drug Resistance, Neoplasm MESH: Dual Specificity Phosphatase 1 / metabolism MESH: Hep G2 Cells MESH: Humans MESH: Intracellular Signaling Peptides and Proteins / metabolism MESH: K562 Cells MESH: MCF-7 Cells MESH: p38 Mitogen-Activated Protein Kinases / metabolism MESH: Protein Serine-Threonine Kinases / metabolism MESH: RNA Processing, Post-Transcriptional MESH: Transcriptome MESH: Tristetraprolin / genetics MESH: Tumor Necrosis Factor-alpha / metabolism Mice Mice, Inbred C57BL Microbial Genetics and Genomics mitogen-activated protein kinase mRNA turnover Mutants p38 Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases - genetics p38 Mitogen-Activated Protein Kinases - metabolism Phosphorylation Plant Genetics and Genomics Post-transcription Post-transcriptional regulation Protein Serine-Threonine Kinases Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Proteome Proteome - genetics Proteome - metabolism Proteomes QH301-705.5 QH426-470 Quiescence relapse RNA Processing, Post-Transcriptional Signal transduction starvation Stem cells THP-1 Cells Transcriptome Translation initiation Tristetraprolin Tristetraprolin - genetics Tristetraprolin - metabolism TTP Tumor Necrosis Factor-alpha Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-α TTP Post-transcriptional regulation AU-rich elements Chemoresistance Quiescence
ISSN:	1474-760X, 1474-7596, 1465-6906, 1474-760X
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Shrnutí:	Background Quiescence (G0) is a transient, cell cycle-arrested state. By entering G0, cancer cells survive unfavorable conditions such as chemotherapy and cause relapse. While G0 cells have been studied at the transcriptome level, how post-transcriptional regulation contributes to their chemoresistance remains unknown. Results We induce chemoresistant and G0 leukemic cells by serum starvation or chemotherapy treatment. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. In G0 cells, canonical translation initiation is inhibited; yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. Importantly, AU-rich elements (AREs) are significantly enriched in the upregulated G0 translatome and transcriptome. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, Tristetraprolin (TTP) in G0. This permits expression of ARE mRNAs that promote chemoresistance. Conversely, inhibition of TTP phosphorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE-bearing TNFα and DUSP1 mRNAs and sensitizes leukemic cells to chemotherapy. Furthermore, co-inhibiting p38 MAPK and TNFα prior to or along with chemotherapy substantially reduces chemoresistance in primary leukemic cells ex vivo and in vivo. Conclusions These studies uncover post-transcriptional regulation underlying chemoresistance in leukemia. Our data reveal the p38 MAPK-MK2-TTP axis as a key regulator of expression of ARE-bearing mRNAs that promote chemoresistance. By disrupting this pathway, we develop an effective combination therapy against chemosurvival.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7011231
ISSN:	1474-760X 1474-7596 1465-6906 1474-760X
DOI:	10.1186/s13059-020-1936-4