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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.

Supplementary Data from RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma

Accurate risk stratification for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is crucial for treatment decisions and prognosis. Here, we introduce a circRNA-based classifier that could improve the prognostic stratification of LA-NPC patients. The circRNAs are identified by microarray profiling, followed by qRT-PCR validation and selection using a machine learning method in the training cohort (n = 170). Based on the proposed classifier, two prognostic-distinctive NPC subtypes are identified, namely the high-risk subtype (subtype H) and low-risk subtype (subtype L), which have significantly different disease-free survival (HR 2.99, 95% CI 1.58-5.67, P < 0.001). Validation in the internal cohort (n = 170) and external cohort (n = 150) yield similar results and the circRNA-based classifier is an independent risk factor of posttreatment relapse. Meanwhile, multiple interdependent features of different subtypes are observed, including relatively higher immune cell infiltration and immune-related pathways activation in subtype L; and predominant stromal, immunosuppressive and tumor-promoting components with moderate immune activation in subtype H. With a less aggressive and more immune-active tumor microenvironment, patients of subtype L could benefit from the addition of induction chemotherapy. In contrast, patients of subtype H, who are vulnerable to chemoresistance, display a strong tendency to benefit from additional immunotherapy. Overall, we define two NPC prognostic subtypes based on a circRNA classifier across multiple cohorts, which exhibit distinct biological ecosystems and suggest opportunities for the personalization of therapeutic regimens. Citation Format: Yelin Liang, Yuheng Zhao, Qian Li, Wei Jiang, Jun Ma, Na Liu, Yingqin Li. Identification and characterization of nasopharyngeal carcinoma prognostic subtypes based on a circRNA classifier: Implications of stratified treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5128.