LncHOXA10 drives liver TICs self-renewal and tumorigenesis via HOXA10 transcription activation

Abstract

BackgroundLiver cancer is one of the most deadly cancers in the world. There are various cells in liver tumor bulk, including liver tumor initiating cells (TICs), which account for liver tumorigenesis, drug resistance, relapse and metastasis. The homeobox (HOX) transcription factors play critical roles in many physiological and pathological processes, while, their roles in liver TICs and liver tumorigenesis remain unknown.MethodsAn unbiased screening was performed using online-available datasets. Liver TICs were sorted by FACS using surface markers CD133, CD13 and EPCAM, or enriched by oncosphere formation assay. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, Western blot and double FISH were used to explore the molecular mechanism of lncRNA.ResultsHere, we examined the expression pattern of HOX transcription factors, and found HOXA10 was overexpressed in liver cancer samples. Moreover, a divergent lncRNA of HOXA10 (termed lncHOXA10 hereafter) was also highly expressed in liver cancer and liver TICs. LncHOXA10 drove liver TIC self-renewal and liver tumorigenesis through HOXA10-dependent manner. LncHOXA10 interacted with SNF2L and recruited NURF chromatin remodeling complex to HOXA10 promoter, and thus initiated the transcription of HOXA10. Through HOXA10 transcriptional regulation, lncHOXA10 activated HOXA10 in liver TICs. LncHOXA10-HOXA10 signaling can be targeted to eliminate liver TICs. Altogether, lncHOXA10 drove HOXA10 expression and thus promoted liver TIC self-renewal.ConclusionHOXA10 was the most highly expressed HOX transcription factor in liver cancer and liver TICs. LncHOXA10 drove the transcriptional activation of HOXA10. This work revealed the important role of HOX transcription factor in liver TIC self-renewal and added a new layer for liver TIC regulation.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0921-y) contains supplementary material, which is available to authorized users.

The Emerging Role of Long Non-Coding RNAs in the Metastasis of Hepatocellular Carcinoma

“…Mechanistically, lncFZD6 directly binds and recruits the BRG1 (Brahma-related Gene 1 protein)-embedded the switch/sucrose non-fermenting (SWI/SNF) complex to the FZD6 promoter, which facilitates the transcription of FZD6 via chromatin remodeling [21]. Similarly, the overexpressed lncHOXA10 recruits the nucleosome remodeling factor (NURF) chromatin remodeling complex to the HOXA10 promoter to initiate the expression of HOXA10, and ultimately promotes the self-renewal of liver TICs and the progression of HCC [22]. Collectively, increasing studies have shown that lncRNAs epigenetically regulate gene transcription by manipulating DNA methylation and histone acetylation.…”

“…In addition, lncRNAs also mediate tumor cells that exhibit unique metabolic phenotypes, such as lncRNA TUG1 (taurine up-regulated gene 1), which exerts a master regulator to coordinate glycolysis and metastasis in HCC [71]. Furthermore, emerging findings revealed that lncRNAs can modulate the transcription of metastasis-related genes to maintain TIC self-renewal and tumor initiation capacity, such as lncSox4 [23], lncFZD6 [21], and lncHOXA10 [22]. Moreover, lncRNA HULC and MALAT1 may promote HCC metastasis via enhancing EMT and migration in the miRNAs/ZEB1 signaling [16,38].…”

Bone-targeted lncRNA OGRU alleviates unloading-induced bone loss via miR-320-3p/Hoxa10 axis

“…Hoxa10, a member of the homeobox gene family, can participate in the development and growth of multiple systems, as indicated by its critical roles in male and female fertility, liver tumorigenesis, gastric cancer invasion and leukemogenesis. [55][56][57][58] Moreover, multiple lines of evidence have shown that Hoxa10 is necessary for the global patterning of the mammalian skeleton. [59][60][61] Furthermore, Hoxa10 can promote osteoblast differentiation through the activation of Runx2 and directly regulate osteoblast differentiation genes, including the alkaline phosphatase, osteocalcin, and bone sialoprotein genes, and this process can be regulated by the Pbx1 complex.…”

LincHOXA10 Facilitates Colorectal Cancer Development By Regulating HOXA10-Mediated Epithelial-Mesenchymal Transtion

“…HOXA10 also takes an important part in embryo implantation [7], endometriosis [8]and hematopoietic lineage commitment [9]. Importantly, HOXA10 is involved in a wide spectrum of biological functions in human cancers, including hepatocellular carcinoma [10,11], lung cancer [12], gastric cancer [13], bladder cancer [14], as well as glioma [15]. However, the expression and role of HOXA10 in CRC has not been previously reported.…”

“…The knockdown of LincHOXA10 expression was shown to induce glioma cell apoptosis [24]. Shao et al found that LincHOXA10 drives liver tumor initiating cells (TICs) self-renewal and tumorigenesis [11]. However, the function and underlying mechanism of LincHOXA10 in the development of CRC remain to be elucidated.…”