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

Résumé fourni par la source

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. Oxidative stress and other signals in the tumor microenvironment initiate LUCAT1 transcription in hepatocellular carcinoma (HCC) cells. In the nucleus, upregulated LUCAT1 binds heat shock protein 90 (HSP90), which maintains constitutive phosphorylation of STAT3 at high levels. These pathways drive HCC growth and metastasis and are ultimately amenable to therapeutic targeting. • LUCAT1 expression is markedly increased in HCC and the levels of expression of LUCAT1 impact the prognosis of HCC. • LUCAT1 localizes within the nucleus and links oxidative stress to HSP90 in HCC cells. • LUCAT1 directly binds to HSP90 and promotes nuclear accumulation. • LUCAT1-HSP90 interactions maintain phosphorylation of STAT3, which is a known major driver of HCC progression. • Antisense oligonucleotides (ASOs) designed to target LUCAT1 have potent anti-tumor activity in vitro and in vivo.

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