ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform

Abstract

The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA NEAT1 as a molecular trigger for ALYREF effects in breast cancer. Mechanistically, we found that ALYREF binds to the NEAT1 promoter region to enhance the global NEAT1 transcriptional activity. Importantly, by stabilizing CPSF6, a protein that selectively activates the post-transcriptional generation of the short isoform of NEAT1, as well as by direct binding and stabilization of the short isoform of NEAT1, ALYREF selectively fine-tunes the expression of the short NEAT1 isoform. Overall, our study describes ALYREF as a novel factor contributing to breast carcinogenesis and identifies novel molecular mechanisms of regulation the two isoforms of NEAT1.

The lncRNA epigenetics: The significance of m6A and m5C lncRNA modifications in cancer

“…ALYREF regulates the expression of the short NEAT1 isoform by binding directly NEAT1 and stabilizing CPSF6. This latter is a protein implicated in the selective activation of the post-transcriptional generation of the short isoform of NEAT1 ( 43 ). ALYREF regulates also the degradation of the unwanted mRNA and lncRNA by nuclear exosome, demonstrated in HeLa and HEK293 cells.…”

Molecular Interactions of the Long Noncoding RNA NEAT1 in Cancer

“…In breast cancer, ALYREF can stabilize CPSF to elevate the NEAT1-1 isoform, promoting carcinogenesis [ 158 ]. Furthermore, another important protein, PTBP3, can increase the expression of NEAT1-2 and total NEAT1 but decrease the induction of miR-612, which has an overlapping sequence with NEAT1-2, as mentioned above.…”

“…Specific proteins are responsible for the stability of NEAT1, including HuR, LIN28B, ALKBH5, PTRF, ALYREF, and SRSF1 [ 158 , 161 , 162 , 163 , 164 , 165 ]. Specifically, HuR and LIN28B can promote ovarian cancer progression via stabilizing NEAT1 [ 161 , 164 ].…”

“…In addition, ALKBH5-stabilized NEAT1 can significantly suppress hypoxia-induced tumor-associated macrophage (TAM) recruitment and immunosuppression in glioblastoma [ 163 ]. ALYREF and SRSF1 can also prolong the half-life of NEAT1, facilitating the progression of breast cancer and glioma, respectively [ 158 , 162 ]. In contrast, AUF1 can destabilize NEAT1 and accelerate its decay in HeLa cells [ 166 ].…”

Epitranscriptomic orchestrations: Unveiling the regulatory paradigm of m6A, A‐to‐I editing, and m5C in breast cancer via long noncoding RNAs and microRNAs

“…The short isoform of NEAT1 serves as a molecular trigger for ALYREF effects in BC, with ALYREF regulating the short NEAT1 isoform by directly binding NEAT1 and stabilizing CPSF6, a protein implicated in selective posttranscriptional generation. 20,107 In 2020, the interaction between DSCAM-AS1 and YBX1 was found to promote cancer progression through the activation of the FOXA1 transcription network in lung adenocarcinoma, breast, and prostate, adding to the repertoire of cancer-associated regulatory networks influenced by m5C. 11 This comprehensive exploration underscores the emerging role of m5C modifications in BC pathogenesis, offering potential diagnostic and therapeutic avenues through the identification of m5C-lncRNAs and their associated readers in the intricate landscape of BC.…”