The long non-coding RNA LncHDAC2 drives the self-renewal of liver cancer stem cells via activation of Hedgehog signaling

Abstract

Background & aims: Liver cancer is the second leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults. The aim of this study was to define the role of the long non-coding RNA lncHDAC2 in the tumorigenesis of HCC.

Methods: CD13⁺CD133⁺ cells (hereafter called liver cancer stem cells [CSCs]) and CD13^-CD133^- cells (referred to as non-CSCs) were sorted from 3 primary HCC tumor tissues and followed by transcriptome microarray. The expression and function of lncHDAC2 were further assessed by northern blot, sphere formation and xenograft tumor models.

Results: LncHDAC2 is highly expressed in HCC tumors and liver CSCs. LncHDAC2 promotes the self-renewal of liver CSCs and tumor propagation. In liver CSCs, lncHDAC2 recruits the NuRD complex onto the promoter of PTCH1 to inhibit its expression, leading to activation of Hedgehog signaling. Moreover, HDAC2 expression levels are positively related to HCC severity and PTCH1 levels are negatively related to HCC severity. Additionally, the Smo inhibitor cyclopamine was shown to impair the self-renewal of liver CSCs and suppress tumor propagation.

Conclusion: Our findings reveal that lncHDAC2 promotes the self-renewal of liver CSCs and tumor propagation by activating the Hedgehog signaling pathway. Downregulating lncHDAC2 is a promising antitumor strategy in HCC.

Lay summary: Liver cancer stem cells harbor high tumor-initiating potential and confer resistance to typical therapies, but the mechanism underlying their self-renewal remains elusive. LncHDAC2 augments the self-renewal of these cells, promoting tumor propagation. In liver cancer stem cells, lncHDAC2 activates Hedgehog signaling to initiate liver tumorigenesis. Therefore, lncHDAC2 and the Hedgehog signaling pathway may serve as biomarkers and potential drug targets for hepatocellular carcinoma.

Keywords: Cancer stem cell; HDAC2; Hepatocellular carcinoma; PTCH1; lncHDAC2.