LncRNA CASC9 promotes esophageal squamous cell carcinoma metastasis through upregulating LAMC2 expression by interacting with the CREB-binding protein

Abstract

Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer. Long noncoding RNAs (lncRNAs) are thought to play a critical role in cancer development. Recently, lncRNA CASC9 was shown to be dysregulated in many cancer types, but the mechanisms whereby this occurs remain largely unknown. In this study, we found that CASC9 was significantly upregulated in ESCC tissues, with further analysis revealing that elevated CASC9 expression was associated with ESCC prognosis and metastasis. Furthermore, we found that CASC9 knockdown significantly repressed ESCC migration and invasion in vitro and metastasis in nude mice in vivo. A microarray analysis and mechanical experiments indicated that CASC9 preferentially affected gene expression linked to ECM–integrin interactions, including LAMC2, an upstream inducer of the integrin pathway. We demonstrated that LAMC2 was consistently upregulated in ESCC and promoted ESCC metastasis. LAMC2 overexpression partially compromised the decrease of cell migration and invasion capacity in CASC9 knockdowns. In addition, we found that both CASC9 and LAMC2 depletion reduced the phosphorylation of FAK, PI3K, and Akt, which are downstream effectors of the integrin pathway. Moreover, the reduction in phosphorylation caused by CASC9 depletion was rescued by LAMC2 overexpression, further confirming that CASC9 exerts a pro-metastatic role through LAMC2. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assay indicated that CASC9 could bind with the transcriptional coactivator CREB-binding protein (CBP) in the nucleus. Chromatin immunoprecipitation (ChIP) assay additionally illustrated that CASC9 increased the enrichment of CBP and H3K27 acetylation in the LAMC2 promoter, thereby upregulating LAMC2 expression. In conclusion, we demonstrate that CASC9 upregulates LAMC2 expression by binding with CBP and modifying histone acetylation. Our research reveals the prognostic and pro-metastatic roles for CASC9 in ESCC, suggesting that CASC9 could serve as a biomarker for prognosis and a target for metastasis treatment.

ELK1‐activated GPC3‐AS1/GPC3 axis promotes the proliferation and migration of cervical cancer cells

“…The next step was to investigate the molecular mechanism by which GPC3‐AS1 and GPC3 were all highly expressed in CC cell lines. Recently, the transcription factor mechanism has attracted the increasing attention as a result of its contribution to the up‐regulation of lncRNA . Hence, we chose four transcription activators (ELK1, STAT3, SP1 and EGR1) to explore whether these factors participate in the up‐regulation mechanism of GPC3‐AS1 and GPC3 in CC cells.…”

Comprehensive bioinformatics analysis identifies lncRNA HCG22 as a migration inhibitor in esophageal squamous cell carcinoma

“…19 Further explorations demonstrated that CASC9 can promote ESCC growth, migration, invasion, and metastasis by regulating molecular pathways, such as LAMC2 and EZH2. 20,21 CASC9 also plays an oncogene in many other malignancies such as gastric cancer and nasopharyngeal cancer. 22,23 Our results confirmed the high expression level of CASC9 in ESCC tumor tissues, and trans-analysis inferred the potential regulatory correlation of CASC9 with MYZAP, a myocardial-related gene.…”

Global analysis of epigenetic heterogeneity identifies divergent drivers of esophageal squamous cell carcinoma

“…Additional studies showed that this lncRNA is overexpressed in multiple types of cancers [38][39][40] . Overexpression of this lncRNA promotes cancer cell growth 50 , invasion 51 and metastasis 52 . Here, we discovered that methylation loss of its promoter is a principle molecular mechanism of ESCCAL-1 dysregulation in ESCC.…”