LncRNA Lnc‐APUE is Repressed by HNF4α and Promotes G1/S Phase Transition and Tumor Growth by Regulating MiR‐20b/E2F1 Axis

Many long noncoding RNAs (lncRNAs) have been annotated, but their functions remain unknown. The authors found a novel lnc‐APUE (lncRNA accelerating proliferation by upregulating E2F1) that is upregulated in different cancer types, including hepatocellular carcinoma (HCC), and high lnc‐APUE level is associated with short recurrence‐free survival (RFS) of HCC patients. Gain‐ and loss‐of‐function analyses showed that lnc‐APUE accelerated G1/S transition and tumor cell growth in vitro and allows hepatoma xenografts to grow faster in vivo. Mechanistically, lnc‐APUE binds to miR‐20b and relieves its repression on E2F1 expression, resulting in increased E2F1 level and accelerated G1/S phase transition and cell proliferation. Consistently, lnc‐APUE level is positively associated with the expression of E2F1 and its downstream target genes in HCC tissues. Further investigations disclose that hepatocyte nuclear factor 4 alpha (HNF4α) binds to the lnc‐APUE promoter, represses lnc‐APUE transcription, then diminishes E2F1 expression and cell proliferation. HNF4α expression is reduced in HCC tissues and low HNF4α level is correlated with high lnc‐APUE expression. Collectively, a HNF4α/lnc‐APUE/miR‐20b/E2F1 axis in which HNF4α represses lnc‐APUE expression and keeps E2F1 at a low level is identified. In tumor cells, HNF4α downregulation leads to lnc‐APUE upregulation, which prevents the inhibition of miR‐20b on E2F1 expression and thereby promotes cell cycle progression and tumor growth.

There exists a HNF4α/lnc‐APUE/miR‐20b/E2F1 regulatory axis, in which HNF4α represses lnc‐APUE expression and keeps E2F1 at a low level. In tumor cells, HNF4α downregulation leads to lnc‐APUE upregulation, which may work as a miR‐20b sponge to prevent the miR‐20b‐mediated repression on E2F1 expression, resulting in increase of E2F1 level and in turn acceleration of G1/S transition and tumor growth.