The lncRNA HOTAIRM1 regulates the degradation of PML-RARA oncoprotein and myeloid cell differentiation by enhancing the autophagy pathway

Abstract

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are of great importance in different cell contexts. However, only a very small number of lncRNAs have been experimentally validated and functionally annotated during human hematopoiesis. Here, we report an lncRNA, HOTAIRM1, which is associated with myeloid differentiation and has pivotal roles in the degradation of oncoprotein PML-RARA and in myeloid cell differentiation by regulating autophagy pathways. We first revealed that HOTAIRM1 has different variants that are expressed at different levels in cells and that the expression pattern of HOTAIRM1 is closely related to that of the PML-RARA oncoprotein in acute promyelocytic leukemia (APL) patients. We further revealed that the downregulation of HOTAIRM1 could inhibit all-trans retinoic acid (ATRA) -induced degradation of PML-RARA in APL cells and repress the process of differentiation from promyelocytic to granulocytic cells. More importantly, we found that HOTAIRM1 regulates autophagy and that autophagosome formation was inhibited when HOTAIRM1 expression was reduced in the cells. Finally, through the use of a dual luciferase activity assay, AGO2 RNA immunoprecipitation and RNA pull-down, HOTAIRM1 was revealed to act as a microRNA sponge in a pathway that included miR-20a/106b, miR-125b and their targets ULK1, E2F1 and DRAM2. We constructed a human APL-ascites SCID mouse model to validate the function of HOTAIRM1 and its regulatory pathway in vivo. This is the first report showing that a lncRNAs regulates autophagy and the degradation of the PML-RARA oncoprotein during the process of myeloid cell differentiation blockade, suggesting that lncRNAs may be the potential therapeutic targets for leukemia.

Acute myeloid leukaemia genomics

“…lncRNAs are able to distinguish different subtypes of human leukaemia and several reports have identified specific patterns of lncRNA expression associated with clinical patient characteristics (Garzon et al , ). At present, two lncRNAs, HOX antisense intergenic RNA myeloid‐specific 1 ( HOTAIRM1 ) and nuclear‐enriched abundant transcript 1 ( NEAT1 ) are known to regulate the differentiation of AML cells (Chen et al , ; Díaz‐Beyá et al , ; Zeng et al , ). HOTAIRM1 is a myeloid‐specific long non‐coding transcript, which is transcribed from the locus between HOXA1 and HOXA2 genes.…”

Regulatory roles of long noncoding RNAs implicated in cancer hallmarks

“…59,152 In contrast to PTENP1, the lncRNA HOTAIRM1 impedes autophagy by inhibiting all-trans retinoic acid (ATRA)-induced cell autophagy of PML-RARA in promyelocytic leukemia (PML). 60,153,154 Interestingly, however, upon binding miR-20a/ 106b and miR-125b for enhancing ULK1, E2F1 and DNA damage regulated autophagy modulator 2 expression, HOTAIRM1 can additionally promote autophagy, contributing to autophagydependent degradation of PML-RARA. 60,155 Thus, overexpression of HOTAIRM1 may serve as a potential therapeutic measure for PML.…”

Transcriptional networks in acute myeloid leukemia

“…262 LncRNAs can also modulate miRNA function in AML by sequestering miRNAs away from their targets. [263][264][265][266] Another class of noncoding RNAs, circular RNAs, which are polyAand lowly expressed with a stable, cell-type and tissue-specific expression 267 and also have a potential role in AML. 268,269 However, these studies are in their infancy and the extent to which circular RNAs dysregulate transcriptional networks remains to be determined.…”