The lncRNA PVT1 regulates nasopharyngeal carcinoma cell proliferation via activating the KAT2A acetyltransferase and stabilizing HIF-1α

Abstract

Long noncoding RNAs (lncRNAs) play important roles in regulating the development and progression of many cancers. However, the clinical significance of specific lncRNAs in the context of nasopharyngeal carcinoma (NPC) and the molecular mechanisms by which they regulate this form of cancer remain largely unclear. In this study we found that the lncRNA PVT1 was upregulated in NPC, and that in patients this upregulation was associated with reduced survival. RNA sequencing revealed that PVT1 was responsible for regulating NPC cell proliferation and for controlling a hypoxia-related phenotype in these cells. PVT1 knockdown reduced NPC cell proliferation, colony formation, and tumorigenesis in a subcutaneous mouse xenograft model systems. We further found that PVT1 serves as a scaffold for the chromatin modification factor KAT2A, which mediates histone 3 lysine 9 acetylation (H3K9), recruiting the nuclear receptor binding protein TIF1β to activate NF90 transcription, thereby increasing HIF-1α stability and promoting a malignant phenotype in NPC cells. Overexpression of NF90 or HIF-1α restored the proliferation in cells that had ceased proliferating due to PVT1 or KAT2A depletion. Conversely, overexpression of active KAT2A or TIF1β, but not of KAT2A acetyltransferase activity-deficient mutants or TIF1β isoforms lacking H3K9ac binding sites, promoted a PVT1-mediated increase in NF90 transcription, as well as increased HIF-1α stability and cell proliferation. PVT1 knockdown enhanced the radiosensitization effect in NPC cells via inhibiting binding between H3K9ac and TIF1β in a manner. Taken together, our results demonstrate that PVT1 serves an oncogenic role and plays an important role in radiosensitivity in malignant NPC via activating the KAT2A acetyltransferase and stabilizing HIF-1α.

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…Some lncRNAs have gradually become important regulators in the development of hypoxic tumors [ 147 ]. In nasopharyngeal carcinoma cells (NPC), both lncRNA PVT1 and lncRNA DANCR can interact with HIF-1α to influence NPC progression [ 148 , 149 ]. Plasmacytoma variant translocation 1 (PVT1) is the first lncRNA gene discovered in Burkitt’s lymphoma, and its lncRNA that has been reported to play a role in promoting tumor progression [ 147 ].…”

“…Plasmacytoma variant translocation 1 (PVT1) is the first lncRNA gene discovered in Burkitt’s lymphoma, and its lncRNA that has been reported to play a role in promoting tumor progression [ 147 ]. PVT1 activates the acetyltransferase KAT2A, and then recruits TIF1β to promote the transcription of NF90 [ 148 ]. This improves the stability of HIF-1α protein and mRNA, and promotes further hypoxia-induced malignant phenotype of NPC [ 148 ].…”

MAGI2‐AS3 rs7783388 polymorphism contributes to colorectal cancer risk through altering the binding affinity of the transcription factor GR to the MAGI2‐AS3 promoter

“…In recent years, CRC with increasing morbidity and mortality rate has become one of the most common malignant tumors 30 . It has been reported that several lncRNAs are aberrantly expressed in CRC and regarded as vital components of cancer risk 31,32 . For instance, Zhang et al 33 identified the downregulation of lncRNA CPS1‐IT1 in CRC cells, and CPS1‐IT1 overexpression suppresses metastasis through inactivating HIF‐1α in CRC.…”

LncRNA SBF2-AS1 Promotes Malignant Phenotypes and Radioresistance of Glioblastoma Cells by Impairing miR-338-3p-targeted MAP4K3 Inhibition

“…Postoperative radiotherapy is one of the main modalities of GBM treatment, but it often fails to achieve the expected results mainly due to tumor radioresistance. Increasing studies showed that lncRNAs have been found to modulate radiosensitivity by regulating various mechanisms [27].Wang et al reported that lncRNA PVT1 served an oncogenic role and played an important role in radiosensitivity in malignant nasopharyngeal carcinoma via activating the KAT2A acetyltransferase and stabilizing HIF-1α [28]. Another study suggested that lncRNA TP73-AS1 was highly expressed in hepatocellular carcinoma and participated in radioresistance via PTEN/AKT signaling pathway [29].…”