Skip to main content

Advertisement

SpringerLink
Log in

Transcriptome Profiling Analysis Identifies LCP1 as a Contributor for Chidamide Resistance in Gastric Cancer

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CFDA:

China Food and Drug Administration

DMEM:

Dulbecco’s Modified Eagle Medium

DMSO:

Dimethyl sulfoxide

DEG:

Differentially expressed gene

FBS:

Fetal bovine serum

FDA:

Food and Drug Administration

GC:

Gastric cancer

HCC:

Hepatocellular carcinoma

HDACi:

Histone deacetylase inhibitor

LCP1:

Lymphocyte cytosolic protein 1

NSCLC:

Non-Small-Cell Lung carcinoma

PC:

Pancreatic cancer (PC)

TSA:

Trichostatin A

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

    Article  PubMed  Google Scholar 

  2. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA: a cancer journal for clinicians. 2016;66(2):115–32. https://doi.org/10.3322/caac.21338.

  3. Eusebi LH, Telese A, Marasco G, Bazzoli F, Zagari RM. Gastric cancer prevention strategies: A global perspective. J Gastroenterol Hepatol. 2020;35(9):1495–502. https://doi.org/10.1111/jgh.15037.

    Article  PubMed  Google Scholar 

  4. Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020;396(10251):635–48. https://doi.org/10.1016/S0140-6736(20)31288-5.

    Article  CAS  PubMed  Google Scholar 

  5. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000;92(15):1210–6.

    Article  CAS  Google Scholar 

  6. Shah RR. Safety and Tolerability of Histone Deacetylase (HDAC) Inhibitors in Oncology. Drug Saf. 2019;42(2):235–45. https://doi.org/10.1007/s40264-018-0773-9.

    Article  CAS  PubMed  Google Scholar 

  7. San-Miguel JF, Hungria VTM, Yoon S-S, Beksac M, Dimopoulos MA, Elghandour A, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195–206. https://doi.org/10.1016/S1470-2045(14)70440-1.

    Article  CAS  PubMed  Google Scholar 

  8. Ning Z-Q, Li Z-B, Newman MJ, Shan S, Wang X-H, Pan D-S, et al. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol. 2012;69(4):901–9. https://doi.org/10.1007/s00280-011-1766-x.

    Article  CAS  PubMed  Google Scholar 

  9. Dong M, Ning ZQ, Xing PY, Xu JL, Cao HX, Dou GF, et al. Phase I study of chidamide (CS055/HBI-8000), a new histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas. Cancer Chemother Pharmacol. 2012;69(6):1413–22. https://doi.org/10.1007/s00280-012-1847-5.

    Article  CAS  PubMed  Google Scholar 

  10. Liu L, Qiu S, Liu Y, Liu Z, Zheng Y, Su X, et al. Chidamide and 5-flurouracil show a synergistic antitumor effect on human colon cancer xenografts in nude mice. Neoplasma. 2016;63(2):193–200. https://doi.org/10.4149/203_150422N214.

    Article  CAS  PubMed  Google Scholar 

  11. Chan TS, Tse E, Kwong Y-L. Chidamide in the treatment of peripheral T-cell lymphoma. Onco Targets Ther. 2017;10:347–52. https://doi.org/10.2147/OTT.S93528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lu X, Ning Z, Li Z, Cao H, Wang X. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China. Intractable Rare Dis Res. 2016;5(3):185–91. https://doi.org/10.5582/irdr.2016.01024.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhou Y, Pan D-S, Shan S, Zhu J-Z, Zhang K, Yue X-P, et al. Non-toxic dose chidamide synergistically enhances platinum-induced DNA damage responses and apoptosis in Non-Small-Cell lung cancer cells. Biomed Pharmacother. 2014;68(4):483–91. https://doi.org/10.1016/j.biopha.2014.03.011.

    Article  CAS  PubMed  Google Scholar 

  14. Wang H, Guo Y, Fu M, Liang X, Zhang X, Wang R, et al. Antitumor activity of Chidamide in hepatocellular carcinoma cell lines. Mol Med Rep. 2012;5(6):1503–8. https://doi.org/10.3892/mmr.2012.858.

    Article  CAS  PubMed  Google Scholar 

  15. Qiao Z, Ren S, Li W, Wang X, He M, Guo Y, et al. Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells. Biochem Biophys Res Commun. 2013;434(1). https://doi.org/10.1016/j.bbrc.2013.03.059.

  16. Zhang W, Niu J, Ma Y, Yang X, Cao H, Guo H, et al. The Synergistic Antitumor Activity of Chidamide in Combination with Bortezomib on Gastric Cancer. Onco Targets Ther. 2020;13:3823–37. https://doi.org/10.2147/OTT.S240721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Luo Se, Ma K, Zhu H, Wang S, Liu M, Zhang W, et al. Molecular, biological characterization and drug sensitivity of chidamide-resistant non-small cell lung cancer cells. Oncol Lett. 2017;14(6):6869–75. https://doi.org/10.3892/ol.2017.7060.

  18. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114–20. https://doi.org/10.1093/bioinformatics/btu170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12(4):357–60. https://doi.org/10.1038/nmeth.3317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Roberts A, Trapnell C, Donaghey J, Rinn JL, Pachter L. Improving RNA-Seq expression estimates by correcting for fragment bias. Genome Biol. 2011;12(3):R22. https://doi.org/10.1186/gb-2011-12-3-r22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28(5):511–5. https://doi.org/10.1038/nbt.1621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Anders S, Pyl PT, Huber W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31(2):166–9. https://doi.org/10.1093/bioinformatics/btu638.

    Article  CAS  PubMed  Google Scholar 

  23. Anders S, Huber W. Differential expression of RNA-Seq data at the gene level – the DESeq package. EMBL. 2013.

  24. Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res. 2008;36(Database issue):D480-D4.

  25. Zeng Q, Li L, Feng Z, Luo L, Xiong J, Jie Z, et al. LCP1 is a prognostic biomarker correlated with immune infiltrates in gastric cancer. Cancer Biomark. 2021;30(1):105–25. https://doi.org/10.3233/CBM-200006.

    Article  CAS  PubMed  Google Scholar 

  26. Zhu Y, Das K, Wu J, Lee MH, Tan P. RNH1 regulation of reactive oxygen species contributes to histone deacetylase inhibitor resistance in gastric cancer cells. Oncogene. 2014;33(12):1527–37. https://doi.org/10.1038/onc.2013.104.

    Article  CAS  PubMed  Google Scholar 

  27. Dedes KJ, Dedes I, Imesch P, von Bueren AO, Fink D, Fedier A. Acquired vorinostat resistance shows partial cross-resistance to “second-generation” HDAC inhibitors and correlates with loss of histone acetylation and apoptosis but not with altered HDAC and HAT activities. Anticancer Drugs. 2009;20(5):321–33. https://doi.org/10.1097/CAD.0b013e3283262a32.

    Article  CAS  PubMed  Google Scholar 

  28. Yamada H, Arakawa Y, Saito S, Agawa M, Kano Y, Horiguchi-Yamada J. Depsipeptide-resistant KU812 cells show reversible P-glycoprotein expression, hyper-acetylated histones, and modulated gene expression profile. Leuk Res. 2006;30(6):723–34.

    Article  CAS  Google Scholar 

  29. Stark R, Grzelak M, Hadfield J. RNA sequencing: the teenage years. Nat Rev Genet. 2019;20(11):631–56. https://doi.org/10.1038/s41576-019-0150-2.

    Article  CAS  PubMed  Google Scholar 

  30. Goldstein D, Djeu J, Latter G, Burbeck S, Leavitt J. Abundant synthesis of the transformation-induced protein of neoplastic human fibroblasts, plastin, in normal lymphocytes. Cancer Res. 1985;45(11 Pt 2):5643–7.

    CAS  PubMed  Google Scholar 

  31. Koide N, Kasamatsu A, Endo-Sakamoto Y, Ishida S, Shimizu T, Kimura Y, et al. Evidence for Critical Role of Lymphocyte Cytosolic Protein 1 in Oral Cancer. Sci Rep. 2017;7:43379. https://doi.org/10.1038/srep43379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Foran E, McWilliam P, Kelleher D, Croke DT, Long A. The leukocyte protein L-plastin induces proliferation, invasion and loss of E-cadherin expression in colon cancer cells. Int J Cancer. 2006;118(8):2098–104.

    Article  CAS  Google Scholar 

  33. Su Kim D, Choi YD, Moon M, Kang S, Lim J-B, Kim KM, et al. Composite three-marker assay for early detection of kidney cancer. Cancer Epidemiol Biomarkers Prev. 2013;22(3):390–8. https://doi.org/10.1158/1055-9965.EPI-12-1156.

    Article  CAS  PubMed  Google Scholar 

  34. Luo W, Schork NJ, Marschke KB, Ng S-C, Hermann TW, Zhang J, et al. Identification of polymorphisms associated with hypertriglyceridemia and prolonged survival induced by bexarotene in treating non-small cell lung cancer. Anticancer Res. 2011;31(6):2303–11.

    CAS  PubMed  Google Scholar 

  35. Janji B, Vallar L, Al Tanoury Z, Bernardin F, Vetter G, Schaffner-Reckinger E, et al. The actin filament cross-linker L-plastin confers resistance to TNF-alpha in MCF-7 breast cancer cells in a phosphorylation-dependent manner. J Cell Mol Med. 2010;14(6A):1264–75. https://doi.org/10.1111/j.1582-4934.2009.00918.x.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEGMENTS AND DISCLOSURES

The authors have declared that they have no competing interests.

Funding

This study was supported by grants from the National Natural Science Foundation of China (No.82160468), Shanghai Science and Technology Innovation Action Plan, Medical Innovation Research Special Project (No.20Y11908400) and The Top-level Clinical Discipline Project of Shanghai Pudong (No. PWYgf2021-07).

Author information

Author notes

  1. Wenfang Bao and Zhe Zhu contributed equally.

Authors and Affiliations

  1. Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, 150 Ji-Mo Rd, Shanghai, 200120, China

    Wenfang Bao, Yong Gao & Jingde Chen

  2. Department of Oncology, Ji’an Hospital, Shanghai East Hospital, Ji’an, 343000, China

    Jingde Chen

  3. Department of Colorectal Surgery, Department of General Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Zhe Zhu

Authors
  1. Wenfang Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhe Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingde Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: Jingde Chen and Yong Gao. Conduction of experiments: Wenfang Bao, Zhe Zhu. Statical analysis and interpretation: Wenfang Bao, Zhe Zhu. Original manuscript drafting and figure construction: Wenfang Bao and Zhe Zhu. Manuscript editing and completion: Jingde Chen. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Yong Gao or Jingde Chen.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 426 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bao, W., Zhu, Z., Gao, Y. et al. Transcriptome Profiling Analysis Identifies LCP1 as a Contributor for Chidamide Resistance in Gastric Cancer. Pharm Res 39, 867–876 (2022). https://doi.org/10.1007/s11095-022-03291-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-022-03291-1

KEY WORDS

Search

Navigation