RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma.

Abstract

PURPOSE:

Epigenetic alterations play important roles in metastasis and drug resistance through gene regulation. However, the functional features and molecular mechanisms of epigenetic changes remain largely unclear in nasopharyngeal carcinoma (NPC) metastasis.

EXPERIMENTAL DESIGN:

Gene regulatory network analysis was used to identify metastatic-specific dysregulated genes between normal and NPC tissues and the expression was validated in published Gene-Expression Omnibus data set. The regulatory and functional role of RAB37 downregulation was examined in NPC and was validated in vitro and in vivo, and downstream target of RAB37 was explored. The clinical value of RAB37 methylation was evaluated in NPC metastasis and chemosensitivity.

RESULTS:

We identified RAB37 as a specific hypermethylated gene that is most commonly downregulated in NPC. Moreover, RAB37 downregulation was attributed to hypermethylation of its promoter and was significantly associated with metastasis- and docetaxel chemoresistance-related features in NPC. Ectopic RAB37 overexpression suppressed NPC cell metastasis and enhanced chemosensitivity to docetaxel. Mechanistically, RAB37 colocalized with TIMP2, regulated TIMP2 secretion, inhibited downstream MMP2 activity, and consequently altered NPC cell metastasis. Furthermore, RAB37 hypermethylation was correlated with poor clinical outcomes in patients with NPC. We developed a prognostic model based on RAB37 methylation and N stage that effectively predicted an increased risk of distant metastasis and a favorable response to docetaxel-containing induction chemotherapy (IC) in NPC patients.

CONCLUSIONS:

This study shows that RAB37 hypermethylation is involved in NPC metastasis and chemoresistance, and that our prognostic model can identify patients who are at a high risk of distant metastasis and might benefit from for docetaxel IC.

• Authors: Yingqin Li, Xiaojing Yang, Xiaojing Du, Yuan Lei, Qingmei He, Xiaohong Hong, Xinran Tang, Xin Wen, Panpan Zhang, Ying Sun, Jian Zhang, Yaqin Wang, Jun Ma, Na Liu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 24 Pg. 6495-6508 (12 15 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 30131385 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• TIMP2 protein, human
• Tissue Inhibitor of Metalloproteinase-2
• Docetaxel
• Matrix Metalloproteinase 2
• Rab37 protein, human
• rab GTP-Binding Proteins

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Computational Biology (methods)
• DNA Methylation
• Docetaxel (administration & dosage)
• Drug Resistance, Neoplasm (genetics)
• Epigenesis, Genetic
• Gene Expression Profiling
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Matrix Metalloproteinase 2 (metabolism)
• Nasopharyngeal Carcinoma (drug therapy, genetics, mortality, pathology)
• Neoplasm Metastasis
• Neoplasm Staging
• Prognosis
• Promoter Regions, Genetic
• Sequence Analysis, DNA
• Tissue Inhibitor of Metalloproteinase-2 (metabolism)
• rab GTP-Binding Proteins (genetics, metabolism)