The long non-coding RNA rhabdomyosarcoma 2-associated transcript exerts anti-tumor effects on lung adenocarcinoma via ubiquitination of SOX9

Yaofei Pei; Bing Zhou; Xiqiang Liu

doi:10.21037/atm-21-6052

The long non-coding RNA rhabdomyosarcoma 2-associated transcript exerts anti-tumor effects on lung adenocarcinoma via ubiquitination of SOX9

Ann Transl Med. 2022 Jan;10(1):10. doi: 10.21037/atm-21-6052.

Authors

Yaofei Pei¹, Bing Zhou², Xiqiang Liu³

Affiliations

¹ Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China.
² Department of Cardiothoracic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
³ Department of Hepatobiliary Surgery and Liver Transplantation Center, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.

Abstract

Background: Long non-coding RNAs (lncRNAs) play an important role in the post-translational modification of proteins, but the importance of lncRNAs in protein ubiquitination remains unclear. This study investigated to role of the lncRNA rhabdomyosarcoma 2-associated transcript (RMST) in lung adenocarcinoma (LUAD).

Methods: The expression of RMST was analyzed in LUAD samples and normal lung tissues using data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) public databases. Colony formation and transwell assays were used to determine the anti-tumor effects of RMST in human LUAD progression. RNA pull-down assays, RNA immunoprecipitation assays, and mass spectrometry were used to determine the mechanisms by which RMST induces the ubiquitination of SRY-box transcription factor 9 (SOX9). Furthermore, animal models were used to determine the effects of RMST on LUAD tumorigenicity in vivo.

Results: Compared with normal tissues, RMST expression was significantly downregulated in LUAD samples. This abnormal expression of RMST led to significant changes in the proliferation and migration of LUAD cells both in vitro and in vivo. The experiments demonstrated that RMST binds directly to the SOX9 protein, resulting in the ubiquitination of SOX9 and this was mediated by F-box and WD repeat domain-containing 7 (FBW7). Clinically, RMST expression was shown to be positively correlated with the overall survival of LUAD patients.

Conclusions: These findings revealed that RMST suppressed the SOX9 signaling pathway to inhibit LUAD growth and metastasis. The RMST-induced ubiquitination of SOX9 via FBW7 may be a potential therapeutic target for the treatment of patients with LUAD.

Keywords: Long non-coding RNA (lncRNA); SRY-box transcription factor 9 (SOX9); lung adenocarcinoma (LUAD); rhabdomyosarcoma 2-associated transcript (RMST); ubiquitin.