Lung cancer associated transcript 1 binds heat shock protein 90 to promote growth of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of leading causes of cancer-related death and new approaches are urgently needed, given current dearth of therapies. Long non-coding RNAs (lncRNAs) have been linked to cancer formation and impact cell regulatory pathways. We have investigated molecular mechanisms of action of “lung cancer associated transcript 1” (LUCAT1, a lncRNA) in HCC and studied the potential role of targeting these. We analyzed expression levels of LUCAT1 in TCGA dataset and another 148 HCC patients in Peking Union Medical College Hospital (PUMCH). Expression analysis using TCGA database and patient cohort revealed LUCAT1 to be upregulated in HCC. LUCAT1 levels were closely associated with clinical prognosis. Subcellular localization patterns of LUCAT1 in HCC tissues and cells were identified by RNAscope. Engineered antisense oligonucleotides (ASOs) targeting LUCAT1 were used to test anti-tumor effectiveness using in vitro and in vivo models. CHIRP-MS and RNA pull-down assays were conducted to demonstrate the mechanism of action of LUCAT1.LUCAT1 expression facilitated nuclear accumulation of HSP90. This interaction evoked persistent phosphorylation and constitutive activation of signal transducer and activator of transcription 3 (STAT3), potentially driving HCC growth and metastases. These tumor-promoting effects were substantively diminished using ASOs against LUCAT1, both in vitro and in vivo. LUCAT1 selectively boosts oncogenic property of HSP90 in driving STAT3 activation, which can be effectively and precisely inhibited by designer ASOs. We propose novel potential therapeutic avenues that are selective, cost-effective and seemingly nontoxic.