Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer
Authors: Peng Liu
Anli Yang
Guanfeng Gao
Hailin Tang
Jie-Ying Liang
Xiaoming Xie
Lu Yang
Shaoquan Zheng
Yutian Zou
Journal: Journal of hematology & oncology (2020)
Discipline: CLINICAL MEDICINE
Keywords: Forkhead box k1; Long non-coding RNA; Lymph node metastasis; Triple-negative breast cancer; Y-box binding protein 1.
Affiliations: Department of Breast Oncology, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, China., State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, Guangdong, China., Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, China., Department of Breast Oncology, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, China. ., State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, 510060, Guangdong, China. .

Abstract:  Background: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with highly invasive ability and metastatic nature to the lymph nodes. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis and progression. However, their roles in TNBC lymph node metastasis remains rarely studied. Methods: The expression of lncRNA highly upregulated in metastatic TNBC (HUMT) in cell lines and tissues was detected by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). RNA immunoprecipitation (RIP) and RNA pulldown were used to verify the interaction between lncRNA and protein. Chromatin immunoprecipitation (CHIP) and dCas9-gRNA-guided chromatin immunoprecipitation (dCas9-CHIP) were conducted to identify the specific binding site of HUMT-YBX1 complex. Western blot was used to detect the downstream of HUMT. Results: HUMT was significantly upregulated in lymph node invasive cells and predicted poorer clinical prognosis. Functional study indicated that HUMT promoted lymphangiogenesis and lymph node metastasis. Bioinformatic analysis and qRT-PCR showed that the high expression of HUMT was correlated with the hypomethylation status of its promoter region. Further, HUMT recruited Y-box binding protein 1 (YBX1) to form a novel transcription complex and activated the expression of forkhead box k1 (FOXK1), thus enhancing the expression of vascular endothelial growth factor C (VEGFC). The therapeutic value was further validated in patient-derived xenograft (PDX) models, and a combined marker panel exhibited a better prognostic value for TNBC in receiver operating characteristic (ROC) analysis. Conclusions: Our study identified a novel TNBC lymph node metastasis-associated lncRNA, which promoted TNBC progression and indicated a novel biomarker and potential therapeutic target for TNBC lymph node metastasis. 

Retracted: No

PubPeer comments:
 Fig 5b, image duplication  , 
 #1 Many thanks for identifying the similarities between these two images. We have checked the original images of Fig. 5b and we confirm that the image of the pcDNA3.1-HUMT-0h group was mistakenly uploaded. We have contacted the editor for corrigendum. We do appreciate your identification of the mistake and the opportunity for us to realize and correct it. ,