HULC cooperates with MALAT1 to aggravate liver cancer stem cells growth through telomere repeat-binding factor 2

Abstract

The dysregulation of lncRNAs has increasingly been linked to many human diseases, especially in cancers. Our results demonstrate HULC, MALAT1 and TRF2 are highly expressed in human hepatocellular carcinoma tissues, and HULC plus MALAT1 overexpression drastically promotes the growth of liver cancer stem cells. Mechanistically, both HULC and MALAT1 overexpression enhanced RNA polII, P300, CREPT to load on the promoter region of telomere repeat-binding factor 2(TRF2), triggering the overexpression, phosphorylation and SUMOylation of TRF2. Strikingly, the excessive TRF2 interacts with HULC or MALAT1 to form the complex that loads on the telomeric region, replacing the CST/AAF and recruiting POT1, pPOT1, ExoI, SNM1B, HP1 α. Accordingly, the telomere is greatly protected and enlonged. Furthermore, the excessive HULC plus MALAT1 reduced the methylation of the TERC promoter dependent on TRF2, increasing the TERC expression that causes the increase of interplay between TRET and TERC. Ultimately, the interaction between RFC and PCNA or between CDK2 and CyclinE, the telomerase activity and the microsatellite instability (MSI) are significantly increased in the liver cancer stem cells. Our demonstrations suggest that haploinsufficiency of HULC/MALAT1 plays an important role in malignant growth of liver cancer stem cell.

Modulation of specific cell cycle phases in human embryonic stem cells by lncRNA RNA decoys

“…Looking into the subnetwork associated with G1‐S phase transition, we identified 2 important lncRNAs (MALAT1 and DANCR), which are previously reported to be involved in the regulation of stem cell properties . These 2 lncRNAs are investigated further to hypothesize their probable role as RNA decoys in G1‐S phase transition of hESCs.…”

“…Looking into the subnetwork associated with G1-S phase transition, we identified 2 important lncRNAs (MALAT1 and DANCR), which are previously reported to be involved in the regulation of stem cell properties. [42][43][44][45][46] These 2 lncRNAs are investigated further to hypothesize their probable role as RNA decoys in G1-S phase transition of hESCs. However, our study could not predict lncPRESS1, a lncRNA which is already known to act as an RNA decoy by interacting with SIRT6 and induce the expressions of pluripotent genes in hESCs to maintain pluripotency 27 as well as few other lncRNAs associated with pluripotency.…”

Inflammatory factor receptor Toll‐like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell

“…Chromatin immunoprecipitation was carried out according to methodology as previously described 26. Briefly, cells were cross‐linked with 1% (v/v) formaldehyde (Sigma‐Aldrich) for 10 minutes at room temperature.…”

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

“…202,203 A recent report showed that long ncRNAs are highly expressed in HCC, and they promote liver cancer stem cell growth through epigenetic regulation. 204 Cheng et al study showed that liver-specific miR-122 is epigenetically suppressed by HOTAIR, leading to activation of Cyclin G1 and HCC growth. 205 Recent research from our laboratory shows that hepatic adaptive response to HCV-induced ER stress and oxidative stress can silence miR-122 through induction of the STAT3-HNF4α-miR-24 inflammatory feedback loop.…”