Truncated HDAC9 identified by integrated genome-wide screen as the key modulator for paclitaxel resistance in triple-negative breast cancer

Autor: Xiao-Guang Li, Zhi-Ming Shao, Mengzhu Xue, Yi-Zi Zheng, Feng Qiao, Yu-Chen Pei, Yi-Zhou Jiang, Min He, Xi-Yu Liu, Wei-Li Sun, Bi Lian, Xin Hu, Da-Qiang Li, Hong Ling, Ling Yao
Rok vydání: 2020
Předmět:
0301 basic medicine
Medicine (miscellaneous)
Datasets as Topic
Apoptosis
Triple Negative Breast Neoplasms
Kaplan-Meier Estimate
CRISPR screen
Transcriptome
Gene Knockout Techniques
Mice
0302 clinical medicine
MITR
Antineoplastic Combined Chemotherapy Protocols
RNA-Seq
Pharmacology
Toxicology and Pharmaceutics (miscellaneous)
Triple-negative breast cancer
MEF2 Transcription Factors
Interleukin-11
paclitaxel resistance
Blot
Gene Expression Regulation
Neoplastic
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Female
Signal Transduction
Research Paper
STAT3 Transcription Factor
Paclitaxel
Cell Survival
Biology
Histone Deacetylases
03 medical and health sciences
breast cancer
In vivo
Cell Line
Tumor
Nitriles
Animals
Humans
Cell Proliferation
Janus Kinases
Cell growth
HDAC9
Xenograft Model Antitumor Assays
In vitro
Repressor Proteins
030104 developmental biology
HEK293 Cells
Pyrimidines
Drug Resistance
Neoplasm
Cancer research
Pyrazoles
Chromatin immunoprecipitation
Zdroj: Theranostics
ISSN: 1838-7640
Popis: Rationale: Paclitaxel resistance is a major concern when treating triple-negative breast cancer (TNBC) patients. We aimed to identify candidates causing paclitaxel resistance and explore their significance in TNBC therapeutics. Methods: A genome-wide CRISPR screening, integrated with transcriptome analyses, was performed to identify candidates involved in paclitaxel-resistant TNBCs. Cell proliferation, cytotoxicity, immunofluorescent staining, and xenograft assays were conducted to verify the phenotypes of paclitaxel resistance induced by candidate genes, both in vitro and in vivo. RNA sequencing, Western blotting, and chromatin immunoprecipitation assays were used to explore the underlying mechanisms. Results: MEF2-interacting transcriptional repressor (MITR), the truncated isoform of histone deacetylase 9 (HDAC9) lacking the deacetylation domain, was enriched in paclitaxel-resistant cells. Elevated MITR expression resulted in increased interleukin-11 (IL11) expression and activation of downstream JAK/STAT3 signaling. Mechanistically, MITR counteracted MEF2A-induced transcriptional suppression of IL11, ultimately causing paclitaxel resistance. By contrast, pharmacological inhibition of JAK1/2 by ruxolitinib reversed paclitaxel resistance both in vitro and in vivo. Conclusion: Our in vitro and in vivo genetic and cellular analyses elucidated the pivotal role of MITR/MEF2A/IL11 axis in paclitaxel resistance and provided a novel therapeutic strategy for TNBC patients to overcome poor chemotherapy responses.
Databáze: OpenAIRE
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