HULC targets the IGF1R–PI3K-AKT axis in trans to promote breast cancer metastasis and cisplatin resistance

• Published in: Cancer letters 2022-11, Vol.548, p.215861-215861, Article 215861
• Main Authors: Zhou, Lei, Li, Hui, Sun, Tingge, Wen, Xue, Niu, Chao, Li, Min, Li, Wei, Hoffman, Andrew R., Hu, Ji-Fan, Cui, Jiuwei
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Acetylation; AKT protein; Animals; Apoptosis - genetics; Breast cancer; CD44 antigen; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Chemotherapy; Chromatin; Cisplatin; Cisplatin - metabolism; Cisplatin - pharmacology; DNA methylation; Epigenetics; Gene Expression Regulation, Neoplastic; Genes; Histones; Histones - metabolism; HULC; IGF1R; Immunodeficiency; Insulin; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Liver cancer; Long noncoding RNA; Medical prognosis; Metastases; Metastasis; Mice; Neoplasm Recurrence, Local - genetics; Non-coding RNA; Oct-4 protein; Phosphatidylinositol 3-Kinases - metabolism; Protein-tyrosine kinase; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - metabolism; Regulatory sequences; Reverse transcription; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA-DNA interactome; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.215861

Insulin-like growth factor I receptor (IGF1R) is frequently upregulated in breast cancer. Due to its intrinsic tyrosine kinase activity, aberrant activation of the IGF1R signaling axis may enhance tumor cell proliferation and cancer stemness, causing tumor relapse, metastasis and resistance to chemotherapy. We utilized a chromatin RNA in situ reverse transcription (CRIST) approach to characterize molecular factors that regulate the IGF1R network. We identified lncRNA HULC (Highly Upregulated in Liver Cancer) as a key trans-regulator of IGF1R in breast cancer cells. Loss of HULC suppressed the expression of IGF1R and the activation of its downstream PI3K/AKT pathway, while HULC overexpression activated the axis in breast cancer cells. Using a transcription-associated trap (RAT) assay, we demonstrated that HULC functioned as a nuclear lncRNA and epigenetically activated IGF1R by directly binding to the intragenic regulatory elements of the gene, orchestrating intrachromosomal interactions, and promoting histone H3K9 acetylation. The activated HULC-IGF1R/PI3K/AKT pathway mediated tumor resistance to cisplatin through the increased expression of cancer stemness markers, including NANOG, SOX2, OCT4, CD44 and ALDH1A1. In immunodeficient mice, stimulation of the HULC-IGF1R pathway promoted tumor metastasis. These data suggest that HULC may be a new epigenetic target for IGF1R axis-targeted therapeutic intervention. •Using a novel “chromatin RNA in situ reverse transcription sequencing” (CRIST-seq) approach, we identify HULC as a trans chromatin RNA molecule that interacts with the IGF1R promoter and regulates its activity in the nucleus.•HULC activates the IGF1R–PI3K-AKT axis, and knockdown of HULC inhibits this signal pathway.•The activated HULC-IGF1R signal enhances the proliferation, metastasis, and cisplatin resistance of breast cancer cells in vitro.•In both the mammary fat pad in situ model and the tail-vein tumor model, HULC promotes tumor metastasis.•Mechanistically, HULC binds to the IGF1R locus and coordinates the intrachromosomal loops between the promoter and intronic enhancer.•The HULC binding controls histone H3K9 acetylation and thus activates the IGF1R promoter.•Our data demonstrate that HULC harnesses a unique trans epigenetic mechanism to control the IGF1R–PI3K-AKT axis in breast cancer cells.