2. Academic Validation
  3. LCAT3, a novel m6A-regulated long non-coding RNA, plays an oncogenic role in lung cancer via binding with FUBP1 to activate c-MYC

LCAT3, a novel m6A-regulated long non-coding RNA, plays an oncogenic role in lung cancer via binding with FUBP1 to activate c-MYC

  • J Hematol Oncol. 2021 Jul 17;14(1):112. doi: 10.1186/s13045-021-01123-0.
Xinyi Qian  # 1,  Juze Yang  # 2,  Qiongzi Qiu  # 1,  Xufan Li 2,  Chengxi Jiang 3,  Jia Li 2,  Liangliang Dong 2,  Kejing Ying 2 4,  Bingjian Lu 1,  Enguo Chen 2 4,  Pengyuan Liu 5 6 7,  Yan Lu 8 9
Affiliations

Affiliations

  • 1 Center for Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China.
  • 2 Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China.
  • 3 Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
  • 4 Cancer Center, Zhejiang University, Hangzhou, 310013, Zhejiang, China.
  • 5 Department of Respiratory Medicine, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, China. pyliu@zju.edu.cn.
  • 6 Cancer Center, Zhejiang University, Hangzhou, 310013, Zhejiang, China. pyliu@zju.edu.cn.
  • 7 Department of Physiology and Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, 53226, WI, USA. pyliu@zju.edu.cn.
  • 8 Center for Uterine Cancer Diagnosis and Therapy Research of Zhejiang Province, Women's Reproductive Health Key Laboratory of Zhejiang Province, Department of Gynecologic Oncology, Women's Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310006, Zhejiang, China. yanlu76@zju.edu.cn.
  • 9 Cancer Center, Zhejiang University, Hangzhou, 310013, Zhejiang, China. yanlu76@zju.edu.cn.
  • # Contributed equally.
PMID: 34274028 DOI: 10.1186/s13045-021-01123-0
Abstract

Background: Long non-coding RNAs (lncRNAs) are important epigenetic regulators, which play critical roles in diverse physiological and pathological processes. However, the regulatory mechanism of lncRNAs in lung carcinogenesis remains elusive. Here, we characterized a novel oncogenic lncRNA, designated as Lung Cancer Associated Transcript 3 (LCAT3).

Methods: We predicted and validated LCAT3 by analyzing RNA-sequencing (RNA-seq) data of lung Cancer tissues from TCGA. Methylated RNA immunoprecipitation was performed to assess m6A modification on LCAT3. The LCAT3-FUBP1-MYC axis was assessed by dual-luciferase reporter, RNA immunoprecipitation and Chromatin immunoprecipitation assays. Signaling pathways altered by LCAT3 knockdown were identified using RNA-seq. Furthermore, the mechanism of LCAT3 was investigated using loss-of-function and gain-of-function assays in vivo and in vitro.

Results: LCAT3 was found to be up-regulated in lung adenocarcinomas (LUAD), and its over-expression was associated with the poor prognosis of LUAD patients. LCAT3 upregulation is attributable to N6-methyladenosine (m6A) modification mediated by methyltransferase like 3 (METTL3), leading to LCAT3 stabilization. Biologically, loss-of-function assays revealed that LCAT3 knockdown significantly suppressed lung Cancer cell proliferation, migration and invasion in vitro, and inhibited tumor growth and metastasis in vivo. LCAT3 knockdown induced cell cycle arrest at the G1 phase. Mechanistically, LCAT3 recruited Far Upstream Element Binding Protein 1 (FUBP1) to the MYC far-upstream element (FUSE) sequence, thereby activating MYC transcription to promote proliferation, survival, invasion and metastasis of lung Cancer cells.

Conclusions: Taken together, we identified and characterized LCAT3 as a novel oncogenic lncRNA in the lung, and validated the LCAT3-FUBP1-MYC axis as a potential therapeutic target for LUAD.

Keywords

FUBP1; LCAT3; Long noncoding RNAs; Lung cancer; MYC; N6-methyladenosine.

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