Journal Article

SUMOylation promotes extracellular vesicle–mediated transmission of lncRNA ELNAT1 and lymph node metastasis in bladder cancer

Zhao, Yue, Huang, Jian, Lin, Tianxin, An, Mingjie, Gao, Bowen, Chen, Changhao, Huang, Hao, Zheng, Hanhao, Luo, Yuming, Li, Yuting, Kong, Yao, He, Wang

2021

Overview

Small ubiquitin-like modifier (SUMO) binding (termed SUMOylation) emerged as the inducer for the sorting of bioactive molecules into extracellular vesicles (EVs), triggering lymphangiogenesis and further driving tumor lymph node (LN) metastasis, but the precise mechanisms remain largely unclear. Here, we show that bladder cancer (BCa) cell-secreted EVs mediated intercellular communication with human lymphatic endothelial cells (HLECs) through transmission of the long noncoding RNA ELNAT1 and promoted lymphangiogenesis and LN metastasis in a SUMOylation-dependent manner in both cultured BCa cell lines and mouse models. Mechanistically, ELNAT1 induced UBC9 overexpression to catalyze the SUMOylation of hnRNPA1 at the lysine 113 residue, which mediated recognition of ELNAT1 by the endosomal sorting complex required for transport (ESCRT) and facilitated its packaging into EVs. EV-mediated ELNAT1 was specifically transmitted into HLECs and epigenetically activated SOX18 transcription to induce lymphangiogenesis. Importantly, blocking the SUMOylation of tumor cells by downregulating UBC9 expression markedly reduced lymphatic metastasis in EV-mediated, ELNAT1-treated BCa in vivo. Clinically, EV-mediated ELNAT1 was correlated with LN metastasis and a poor prognosis for patients with BCa. These findings highlight a molecular mechanism whereby the EV-mediated ELNAT1/UBC9/SOX18 regulatory axis promotes lymphangiogenesis and LN metastasis in BCa in a SUMOylation-dependent manner and implicate ELNAT1 as an attractive therapeutic target for LN metastatic BCa.

• Publisher: American Society for Clinical Investigation
• Subject: Animal models / Animals / Biomedical research / Bladder cancer / Care and treatment / Cell culture / Cell interactions / Cell Line, Tumor / Cell signaling / Development and progression / Endothelial cells / Extracellular vesicles / Extracellular Vesicles - genetics / Extracellular Vesicles - metabolism / Extracellular Vesicles - pathology / Female / Gene expression / Genetic aspects / Health aspects / Humans / Lymph nodes / Lymphatic Metastasis / Lymphatic system / Lysine / Male / Medical prognosis / Metastases / Metastasis / Mice / Mice, Inbred BALB C / Mice, Nude / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Neovascularization / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / RNA, Neoplasm - genetics / RNA, Neoplasm - metabolism / Signal transduction / SUMO protein / Sumoylation / Therapeutic targets / Transcription / Tumor cells / Ubiquitin / Urinary Bladder Neoplasms - genetics / Urinary Bladder Neoplasms - metabolism / Urinary Bladder Neoplasms - pathology