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Transcriptome analysis reveals the molecular mechanisms of combined gamma-tocotrienol and hydroxychavicol in preventing the proliferation of 1321N1, SW1783, and LN18 glioma cancer cells

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Abstract

Gamma-tocotrienol (GTT) and hydroxychavicol (HC) exhibit anticancer activity in glioma cancer cells, where the combination of GTT + HC was shown to be more effective than single agent. The aim of this study was to determine the effect of GTT + HC by measuring the cell cycle progression, migration, invasion, and colony formation of glioma cancer cells and elucidating the changes in gene expression mitigated by GTT + HC that are critical to the chemoprevention of glioma cell lines 1321N1 (grade II), SW1783 (grade III), and LN18 (grade IV) using high-throughput RNA sequencing (RNA-seq). Results of gene expression levels and alternative splicing transcripts were validated by qPCR. Exposure of glioma cancer cells to GTT + HC for 24 h promotes cell cycle arrest at G2M and S phases and inhibits cell migration, invasion, and colony formation of glioma cancer cells. The differential gene expression induced by GTT + HC clustered into response to endoplasmic reticulum (ER) stress, cell cycle regulations, apoptosis, cell migration/invasion, cell growth, and DNA repair. Subnetwork analysis of genes altered by GTT + HC revealed central genes, ATF4 and XBP1. The modulation of EIF2AK3, EDN1, and FOXM1 were unique to 1321N1, while CSF1, KLF4, and FGF2 were unique to SW1783. PLK2 and EIF3A gene expressions were only altered in LN18. Moreover, GTT + HC treatment dynamically altered transcripts and alternative splicing expression. GTT + HC showed therapeutic potential against glioma cancer as evident by the inhibition of cell cycle progression, migration, invasion, and colony formation of glioma cancer cells, as well as the changes in gene expression profiles with key targets in ER unfolded protein response pathway, apoptosis, cell cycle, and migration/invasion.

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Data availability

The datasets used and/or analyzed during this study are included in the supplementary information files. The RNA-seq dataset for 1321N1, SW1783, and LN18 cell lines (for vehicle control, GTT, HC, and GTT + HC groups, N = 36) have been deposited in the NCBI SRA with BioProject accession number PRJNA545804 (https://www.ncbi.nlm.nih.gov/bioproject/545804).

Abbreviations

GTT:

Gamma-tocotrienol

HC:

Hydroxychavicol

ER:

Endoplasmic reticulum

MTC:

Multiple testing correction

FDR:

Benjamini–Hochberg false discovery rate

GSEA:

Gene significant enrichment analysis

FET:

Fisher exact test

UPR:

Unfolded protein response

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Acknowledgments

The authors would like to thank Mohd Faizal Abu Bakar from Malaysian Genome Institute (MGI), Kajang, Malaysia, for his technical assistance with mRNA-Seq analysis and Irni Sahayu Sapian from MGI, Malaysia, for her technical assistance with handling the RNA-Seq equipment.

Funding

This study was supported by the Higher Institutions Centre of Excellence (HICoE) grant (Grant No.: 10-64-01-005) from the Ministry of Higher Education, Malaysia.

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Authors and Affiliations

  1. Department Biochemistry & Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA, Cawangan Selangor, Kampus Sungai Buloh, Jalan Hospital, 47000, Sungai Buloh, Selangor, Malaysia

    Amirah Abdul Rahman

  2. UKM Medical Molecular Biology Institute (UMBI), UKM Medical Center, Jalan Ya’acob, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia

    Amirah Abdul Rahman & Rahman Jamal

  3. Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Ya’acob, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia

    Norfilza Mohd Mokhtar

  4. KPJ Ampang Putri Hospital, 1 Jalan Mamanda 9, Taman Dato Ahmad Razali, 68000, Ampang, Selangor, Malaysia

    Roslan Harun

  5. Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Ya’acob, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia

    Wan Zurinah Wan Ngah

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  1. Amirah Abdul Rahman
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  2. Norfilza Mohd Mokhtar
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  4. Rahman Jamal
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AAR performed experiments, analysis, and interpretation of data and wrote the manuscript. RJ, RH, and NMM were involved in the general supervision. WZWN designed the study, revised the manuscript, and supervised the study. All authors have read and approved the manuscript.

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Correspondence to Norfilza Mohd Mokhtar.

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Abdul Rahman, A., Mokhtar, N.M., Harun, R. et al. Transcriptome analysis reveals the molecular mechanisms of combined gamma-tocotrienol and hydroxychavicol in preventing the proliferation of 1321N1, SW1783, and LN18 glioma cancer cells. J Physiol Biochem 75, 499–517 (2019). https://doi.org/10.1007/s13105-019-00699-z

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