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Transcriptome Profiling Analysis Identifies LCP1 as a Contributor for Chidamide Resistance in Gastric Cancer
Wenfang Bao1, Zhe Zhu2, Yong Gao3
1Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, 150 Ji-Mo Rd, Shanghai, 200120, China.
Background:
Gastric cancer (GC) remains a significant health problem and carries with it substantial morbidity and mortality. Chidamide is a novel and orally administered histone deacetylase (HDAC) inhibitor and has been demonstrated its anti-tumor efficacy on different kinds of hematological and solid tumors. However, the underlying mechanism of chidamide resistance is still poorly characterized.
Methods:
We established chidamide resistant GC cell lines, AGS ChiR and MGC803 ChiR and investigated the toxicologic effects through cell survival, colony formation and flow cytometry assays in vitro, and a subcutaneous xenograft model in vivo. RNA-sequence was then performed to screen chidamide resistance-associated genes between AGS and AGS ChiR cells. The role of Lymphocyte cytosolic protein 1 (LCP1) in chidamide resistance was explored by gain- and loss-of-function analyses.
Results:
We found that chidamide significantly inhibited cell proliferation and induced the apoptosis in a concentration-dependent manner in wild-type GC cell lines as compared to chidamide resistant cell lines. The transcriptomic profiling, quantitative RT-PCR, and western blot data revealed that LCP1 was upregulated in AGS ChiR cells compared with parental cells. Overexpression of LCP1 conferred and knockdown of LCP1 attenuated the chidamide resistance of GC cells. Epigenetic derepression of LCP1 by chidamide may be a possible reason for the contribution of LCP1 to chidamide resistance.
Conclusions:
These findings illustrated that LCP1 may play a chidamide resistance role in GC, suggesting that LCP1 could be a potential target for the therapy of GC combined with chidamide.
Insights
Chidamide resistance in gastric cancer (GC) involves increased Lymphocyte cytosolic protein 1 (LCP1). Targeting LCP1 may improve chidamide therapy for GC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Gastric cancer (GC) presents a significant global health challenge with high morbidity and mortality.
- Chidamide, an oral histone deacetylase (HDAC) inhibitor, shows anti-tumor effects, but its resistance mechanisms in GC are unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying chidamide resistance in gastric cancer.
- To identify potential therapeutic targets for overcoming chidamide resistance in GC.
Main Methods:
- Established chidamide-resistant gastric cancer cell lines (AGS ChiR, MGC803 ChiR).
- Performed in vitro (cell survival, colony formation, flow cytometry) and in vivo (xenograft model) toxicity assessments.
- Utilized RNA-sequencing to identify resistance-associated genes and conducted gain/loss-of-function studies for Lymphocyte cytosolic protein 1 (LCP1).
Main Results:
- Chidamide effectively inhibited proliferation and induced apoptosis in wild-type GC cells but not resistant lines.
- Lymphocyte cytosolic protein 1 (LCP1) was significantly upregulated in chidamide-resistant cells.
- LCP1 overexpression enhanced chidamide resistance, while LCP1 knockdown sensitized cells to chidamide, suggesting LCP1's role in resistance, potentially via epigenetic derepression.
Conclusions:
- Lymphocyte cytosolic protein 1 (LCP1) plays a crucial role in mediating chidamide resistance in gastric cancer.
- LCP1 represents a potential therapeutic target for combination therapy to enhance chidamide efficacy in treating GC.
