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The transcription factor HIF-1 induces the expression of genes that are essential for cell survival and oxygen homeostasis in hypoxic conditions. The prolyl isomerase Pin1 plays a role in the regulation of HIF-1α. However, the mechanism by which Pin1 controls HIF-1α remains controversial. Surprisingly, we here show that a  PIN1  transcript downregulates HIF-1α as a long non-coding RNA. Pin1-silencing siRNAs augmented the hypoxia-induced expression of HIF-1α, thereby upregulating the expression of HIF-1 target genes. However, the overexpression of Pin1 protein did not inhibit the hypoxic expression of HIF-1α. Pin1 restoration in Pin1-depleted cells also failed to reverse the induction of HIF-1α by Pin1 knockdown. Unexpectedly, HIF-1α was found to be induced by both siRNAs for  PIN1  transcript variants 1/2 and that for  PIN1  transcript variants 2/3, indicating that the  PIN1  transcript variant 2 ( PIN1 -v2) is responsible for HIF-1α induction. Mechanistically,  PIN1 -v2, which is classified as a long non-coding RNA due to early termination of translation, was evaluated to inhibit the transcription of  HIF1A  gene. In conclusion,  PIN1 -v2 may function in balancing the HIF-1-driven gene expression under hypoxia.

PIN1 transcript variant 2 acts as a long non-coding RNA that controls the HIF-1-driven hypoxic response