LncRNA CALML3-AS1 Modulated by MA Modification Induces BTNL9 Methylation to Drive Non-small-cell Lung Cancer Progression

Overview

Journal Cancer Gene Ther

Specialties Genetics
Oncology
Pharmacology

Date 2023 Oct 26

PMID 37884580

Authors

Heng Zhang

Shao-Qiang Wang

Jie-Bo Zhu

Li-Na Wang

Hang Lin

Lin-Feng Li

Yuan-Da Cheng

Chao-Jun Duan

Chun-Fang Zhang

Affiliations

Soon will be listed here.

Abstract

Non-small cell lung cancer (NSCLC) is a common and lethal malignancy. The carcinogenic roles of lncRNA CALML3 antisense RNA 1 (CALML3-AS1) have been documented. However, the function and potential mechanisms of CALML3-AS1 in the progression of NSCLC need to be further explored. The molecule expression was assessed by qRT-PCR and Western blot. The subcellular localization of CALML3-AS1 was observed by fluorescence in situ hybridization (FISH). The malignant behaviors of NSCLC cells were evaluated by CCK-8, colony formation, EdU, wound healing and transwell assays. In vivo xenograft tumor and liver metastatic models were established. The molecular mechanisms were investigated by RIP, RNA pull-down and ChIP assays. The methylation level was detected by MSP. Herein, we found that CALML3-AS1 was upregulated, while butyrophilin-like 9 (BTNL9) was downregulated in NSCLC. Functionally, CALML3-AS1 depletion repressed NSCLC cell malignant phenotypes, in vivo tumor growth, and liver metastasis. Mechanistically, AlkB homolog 5 (ALKBH5) enhanced CALML3-AS1 stability via N-methyladenosine (mA) demethylation, whereas mA reader YTH domain-containing 2 (YTHDC2) destabilized CALML3-AS1. Moreover, CALML3-AS1 inhibited BTNL9 transcription and expression through the recruitment of Zeste homolog 2 (EZH2). Rescue experiments demonstrated that BTNL9 downregulation counteracted sh-CALML3-AS1-mediated antitumor effects on NSCLC. Taken together, CALML3-AS1 modulated by ALKBH5 and YTHDC2 in an mA modification dependent manner drives NSCLC progression via epigenetically repressing BTNL9.

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