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

• Published in: Scientific reports 2019-07, Vol.9 (1), p.10599-9, Article 10599
• Main Authors: Choi, Yong-Joon, Kim, Iljin, Lee, Jae Eun, Park, Jong-Wan
• Format: Article
• Language: English
• Subjects: 38/1; 38/109; 38/77; 38/89; 631/337/384/2568; 631/80/304; 82/80; Blotting, Western; Cell Line; Cell survival; Chromatin Immunoprecipitation; Gene expression; Homeostasis; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia - metabolism; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - metabolism; Hypoxia-Inducible Factor 1 - physiology; multidisciplinary; NIMA-Interacting Peptidylprolyl Isomerase - metabolism; NIMA-Interacting Peptidylprolyl Isomerase - physiology; Non-coding RNA; Peptidylprolyl isomerase; Pin1 protein; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Long Noncoding - metabolism; RNA, Long Noncoding - physiology; RNA-mediated interference; Science; Science (multidisciplinary); siRNA; Translation termination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-47071-1

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.