HDAC5, an early osimertinib-responsive gene, is a novel therapeutic target for the drug resistance in EGFR-mutant lung adenocarcinoma cells
Aberrant epigenetic regulation is closely associated with drug tolerance, an early step in the acquisition of drug resistance. We previously reported that a pioneer transcriptional factor (also called an epigenetic initiator) rapidly induced by osimertinib, a third-generation epidermal growth factor...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
|
| Series: | Biochemistry and Biophysics Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580825001037 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850184084759773184 |
|---|---|
| author | Hanbing Lyu Akihiko Ishimura Ryusuke Suzuki Khurelsukh Buyanbat Gerelsuren Batbayar Makiko Meguro-Horike Shin-ichi Horike Seiji Yano Takeshi Suzuki |
| author_facet | Hanbing Lyu Akihiko Ishimura Ryusuke Suzuki Khurelsukh Buyanbat Gerelsuren Batbayar Makiko Meguro-Horike Shin-ichi Horike Seiji Yano Takeshi Suzuki |
| author_sort | Hanbing Lyu |
| collection | DOAJ |
| description | Aberrant epigenetic regulation is closely associated with drug tolerance, an early step in the acquisition of drug resistance. We previously reported that a pioneer transcriptional factor (also called an epigenetic initiator) rapidly induced by osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, plays a pivotal role in promoting the formation of osimertinib-tolerant cells. In this study, to identify novel epigenetic factors associated with osimertinib-tolerance, we performed a comprehensive screening of epigenetic factors whose expression is rapidly induced by osimertinib. Our results revealed that HDAC5, a class IIa histone deacetylase (HDAC), is a prominently induced epigenetic regulator in several EGFR-mutant non-small cell lung cancer (NSCLC) cell lines during the early response to osimertinib. Knockdown of HDAC5 significantly reduced the emergence of osimertinib-resistant cells. Furthermore, treatment with LMK235, a selective HDAC5 inhibitor, significantly increased global histone acetylation and enhanced osimertinib-induced apoptosis. These findings highlight the potential of HDAC5 as a novel therapeutic target to overcome osimertinib-resistance and suggest LMK235 as a promising compound to provide therapeutic benefit to EGFR-mutant NSCLC patients receiving osimertinib treatment. |
| format | Article |
| id | doaj-art-54d5786302cd44849b60e65e4850a62c |
| institution | OA Journals |
| issn | 2405-5808 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj-art-54d5786302cd44849b60e65e4850a62c2025-08-20T02:17:09ZengElsevierBiochemistry and Biophysics Reports2405-58082025-06-014210201610.1016/j.bbrep.2025.102016HDAC5, an early osimertinib-responsive gene, is a novel therapeutic target for the drug resistance in EGFR-mutant lung adenocarcinoma cellsHanbing Lyu0Akihiko Ishimura1Ryusuke Suzuki2Khurelsukh Buyanbat3Gerelsuren Batbayar4Makiko Meguro-Horike5Shin-ichi Horike6Seiji Yano7Takeshi Suzuki8Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kanazawa, JapanDivision of Functional Genomics, Cancer Research Institute, Kanazawa University, Kanazawa, JapanDivision of Functional Genomics, Cancer Research Institute, Kanazawa University, Kanazawa, JapanDivision of Functional Genomics, Cancer Research Institute, Kanazawa University, Kanazawa, JapanLaboratory of Molecular Biology, Institute of Biology, Mongolian Academy of Sciences, MongoliaDivision of Integrated Omics Research, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, JapanDivision of Integrated Omics Research, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa, JapanDepartment of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa, JapanDivision of Functional Genomics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Corresponding author. Division of Functional Genomics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.Aberrant epigenetic regulation is closely associated with drug tolerance, an early step in the acquisition of drug resistance. We previously reported that a pioneer transcriptional factor (also called an epigenetic initiator) rapidly induced by osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, plays a pivotal role in promoting the formation of osimertinib-tolerant cells. In this study, to identify novel epigenetic factors associated with osimertinib-tolerance, we performed a comprehensive screening of epigenetic factors whose expression is rapidly induced by osimertinib. Our results revealed that HDAC5, a class IIa histone deacetylase (HDAC), is a prominently induced epigenetic regulator in several EGFR-mutant non-small cell lung cancer (NSCLC) cell lines during the early response to osimertinib. Knockdown of HDAC5 significantly reduced the emergence of osimertinib-resistant cells. Furthermore, treatment with LMK235, a selective HDAC5 inhibitor, significantly increased global histone acetylation and enhanced osimertinib-induced apoptosis. These findings highlight the potential of HDAC5 as a novel therapeutic target to overcome osimertinib-resistance and suggest LMK235 as a promising compound to provide therapeutic benefit to EGFR-mutant NSCLC patients receiving osimertinib treatment.http://www.sciencedirect.com/science/article/pii/S2405580825001037HDAC5LMK235Lung cancerEGFR-TKIOsimertinibDrug resistance |
| spellingShingle | Hanbing Lyu Akihiko Ishimura Ryusuke Suzuki Khurelsukh Buyanbat Gerelsuren Batbayar Makiko Meguro-Horike Shin-ichi Horike Seiji Yano Takeshi Suzuki HDAC5, an early osimertinib-responsive gene, is a novel therapeutic target for the drug resistance in EGFR-mutant lung adenocarcinoma cells Biochemistry and Biophysics Reports HDAC5 LMK235 Lung cancer EGFR-TKI Osimertinib Drug resistance |
| title | HDAC5, an early osimertinib-responsive gene, is a novel therapeutic target for the drug resistance in EGFR-mutant lung adenocarcinoma cells |
| title_full | HDAC5, an early osimertinib-responsive gene, is a novel therapeutic target for the drug resistance in EGFR-mutant lung adenocarcinoma cells |
| title_fullStr | HDAC5, an early osimertinib-responsive gene, is a novel therapeutic target for the drug resistance in EGFR-mutant lung adenocarcinoma cells |
| title_full_unstemmed | HDAC5, an early osimertinib-responsive gene, is a novel therapeutic target for the drug resistance in EGFR-mutant lung adenocarcinoma cells |
| title_short | HDAC5, an early osimertinib-responsive gene, is a novel therapeutic target for the drug resistance in EGFR-mutant lung adenocarcinoma cells |
| title_sort | hdac5 an early osimertinib responsive gene is a novel therapeutic target for the drug resistance in egfr mutant lung adenocarcinoma cells |
| topic | HDAC5 LMK235 Lung cancer EGFR-TKI Osimertinib Drug resistance |
| url | http://www.sciencedirect.com/science/article/pii/S2405580825001037 |
| work_keys_str_mv | AT hanbinglyu hdac5anearlyosimertinibresponsivegeneisanoveltherapeutictargetforthedrugresistanceinegfrmutantlungadenocarcinomacells AT akihikoishimura hdac5anearlyosimertinibresponsivegeneisanoveltherapeutictargetforthedrugresistanceinegfrmutantlungadenocarcinomacells AT ryusukesuzuki hdac5anearlyosimertinibresponsivegeneisanoveltherapeutictargetforthedrugresistanceinegfrmutantlungadenocarcinomacells AT khurelsukhbuyanbat hdac5anearlyosimertinibresponsivegeneisanoveltherapeutictargetforthedrugresistanceinegfrmutantlungadenocarcinomacells AT gerelsurenbatbayar hdac5anearlyosimertinibresponsivegeneisanoveltherapeutictargetforthedrugresistanceinegfrmutantlungadenocarcinomacells AT makikomegurohorike hdac5anearlyosimertinibresponsivegeneisanoveltherapeutictargetforthedrugresistanceinegfrmutantlungadenocarcinomacells AT shinichihorike hdac5anearlyosimertinibresponsivegeneisanoveltherapeutictargetforthedrugresistanceinegfrmutantlungadenocarcinomacells AT seijiyano hdac5anearlyosimertinibresponsivegeneisanoveltherapeutictargetforthedrugresistanceinegfrmutantlungadenocarcinomacells AT takeshisuzuki hdac5anearlyosimertinibresponsivegeneisanoveltherapeutictargetforthedrugresistanceinegfrmutantlungadenocarcinomacells |