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Background  Many studies have reported the roles of the extracellular hypoxia microenvironment in the tumorigenesis and metastasis of multiple cancers. However, long noncoding RNAs ( lncRNA s) that induce cancer oncogenicity and metastasis of pancreatic cancer (PC) under hypoxia conditions remain unclear.    Methods  In PC cells, the expression levels of  lncRNA s in different conditions (normoxia or hypoxia) were compared through RNA sequencing (RNA-seq). The effects of the zinc finger E-box-binding homeobox 1 ( ZEB1-AS1 ) antisense  lncRNA  on PC cells cultured in normoxia/hypoxia medium were measured through gain and loss-of-function experiments. Fluorescence  in situ  hybridization and luciferase reporter assays in addition to  in vivo  studies were utilized to explore the adaptive mechanisms of  ZEB1-AS1  in the hypoxia-promoted proliferation, migration, and invasion ability of PC cells. Moreover, the level of  ZEB1-AS1  and its associated targets or pathways were investigated in both PC and pancreatic normal tissues.    Results  RNA-seq revealed that  ZEB1-AS1  was significantly upregulated in PC cells under hypoxia conditions. The  ZEB1-AS1  expression level was closely associated with poor prognosis of PC patients. Knockdown of  ZEB1-AS1  suppressed the proliferation, migration, and invasion of PC cells  in vitro  as well as PC xenograft tumor growth  in vivo . In PC cells, RNAi-mediated reduction of  ZEB1-AS1  inhibited zinc finger E-box-binding homeobox 1 ( ZEB1 ), while  ZEB1-AS1  overexpression rescued  ZEB1  expression, indicating that  ZEB1-AS1  promotes  ZEB1  expression. Moreover, hypoxia-inducible factor-1α ( HIF-1 α)induced the expression of  ZEB1-AS1  by binding to the  ZEB1-AS1  promoter, which contains a putative hypoxia response element (HRE). Mechanistically,  ZEB1-AS1  scaffolded the interaction among  HIF-1 α,  ZEB1 , and histone deacetylase 1 ( HDAC1 ), leading to deacetylation-mediated stabilization of  HIF-1 α. We further revealed that  ZEB1  induced the deacetylase capacity of  HDAC1  to suppress the acetylation or degradation of  HIF-1 α, improving  HIF-1 α assembly. Thus, hypoxia-induced  ZEB1-AS1  facilitated  ZEB1  transcription and the stability of  HIF-1 α, which promoted the metastasis of PC cells. Clinically, dysregulated  ZEB1  and  HIF-1 α expression was significantly correlated with histological grade, lymphatic metastasis, and distant metastasis in PC patients.    Conclusions  Our results emphasized that the positive reciprocal loop of  HIF-1 α/ ZEB1-AS1 / ZEB1 / HDAC1  contributes to hypoxia-promoted oncogenicity and PC metastasis, indicating that it might be a novel therapeutic target for PC.

Positive Reciprocal Feedback of lncRNA ZEB1-AS1 and HIF-1α Contributes to Hypoxia-Promoted Tumorigenesis and Metastasis of Pancreatic Cancer