Hypoxia-induced LncRNA DACT3-AS1 upregulates PKM2 to promote metastasis in hepatocellular carcinoma through the HDAC2/FOXA3 pathway

Growing evidence has revealed that hypoxia is involved in multiple stages of cancer development. However, there are limited reports on the effects of long noncoding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) progression under hypoxia. The main purposes of this study were to analyze the effect of the novel lncRNA DACT3-AS1 on metastasis in HCC and to elucidate the related molecular mechanism. Bioinformatics tools were employed. RT-qPCR or western blot assays were conducted to detect RNA or protein expression. Clinical samples and in vivo assays were utilized to reveal the role of DACT3-AS1 in HCC. Other mechanism and functional analyses were specifically designed and performed as well. Based on the collected data, this study revealed that HIF-1 alpha transcriptionally activates DACT3-AS1 expression under hypoxia. DACT3-AS1 was verified to promote metastasis in HCC. Mechanistically, DACT3-AS1 promotes the interaction between HDAC2 and FOXA3 to stimulate FOXA3 deacetylation, which consequently downregulates the FOXA3 protein. Furthermore, FOXA3 serves as a transcription factor that can bind to the PKM2 promoter region, thus hindering PKM2 expression. To summarize, this study uncovered that HIF-1 alpha-induced DACT3-AS1 promotes metastasis in HCC and can upregulate PKM2 via the HDAC2/FOXA3 pathway in HCC cells. Liver cancer: role of non-coding RNA in cancer spread Understanding the role of an RNA molecule involved in metastasis (spread) of liver cancer may suggest potential therapeutic targets. Hepatocarcinoma is a common primary liver cancer, and mortality remains high due to late diagnosis and the risk of metastasis. Scientists believe hypoxic (low oxygen) conditions in solid tumors may trigger metastasis by a mechanism involving long non-coding RNAs. Bin Li and co-workers at the Affiliated Hospital of Guilin Medical College, China, used patient tissue samples to examine the role of the long non-coding RNA molecule DACT3-AS1 in promoting hepatocarcinoma metastasis. Hypoxia triggers the overexpression of HIF-1 alpha. This protein activated DACT3-AS1, which was then highly expressed in metastatic tissues. DACT3-AS1 interacted with a nearby gene and associated enzyme to promote cell migration and invasion, hinting at possible treatment options.