The EMBO Journal, 23 July, 2019，DOI：https://doi.org/10.15252/embj.2018101110
LncRNA HAND2‐AS1 promotes liver cancer stem cell self‐renewal via BMP signaling
Yanying Wang, Pingping Zhu, Jianjun Luo, Jing Wang, Zhiwei Liu, Wei Wu, Ying Du, Buqing Ye, Dongpeng Wang, Lei He, Weizheng Ren, Jianyi Wang, Xianhui Sun, Runsheng Chen, Yong Tian, Zusen Fan
Hepatocellular carcinoma (HCC) is the most prevalent liver cancer, characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well contribute to both of these pathological properties, but the mechanism underlying their self‐renewal maintenance is poorly understood. Here, we identified a long noncoding RNA (lncRNA) termed HAND2‐AS1 that is highly expressed in liver CSCs. Human HAND2‐AS1 and its mouse ortholog lncHand2 display a high level of conservation. HAND2‐AS1 is required for the self‐renewal maintenance of liver CSCs to initiate HCC development. Mechanistically, HAND2‐AS1 recruits the INO80 chromatin‐remodeling complex to the promoter of BMPR1A, thereby inducing its expression and leading to the activation of BMP signaling. Importantly, interfering with expression of HAND2‐AS1 by antisense oligonucleotides (ASOs) and BMPR1A by siRNAs has synergistic anti‐tumorigenic effects on humanized HCC models. Moreover, knockout of lncHand2 or Bmpr1a in mouse hepatocytes impairs BMP signaling and suppresses the initiation of liver cancer. Our findings reveal that HAND2‐AS1 promotes the self‐renewal of liver CSCs and drives liver oncogenesis, offering a potential new target for HCC therapy.