Hypoxia-induced loss of SRSF2-dependent DNA methylation promotes CTCF-mediated alternative splicing of VEGFA in breast cancer

Yadav, Pooja; Pandey, Anchala; Kakani, Parik; Mutnuru, Srinivas Abhishek; Samaiya, Atul; Mishra, Jharna; Shukla, Sanjeev

doi:10.1016/j.isci.2023.106804

Cited by 8 publications

(2 citation statements)

References 57 publications

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“…Over the course of evolution, humans and other organisms have developed mechanisms for sensing and adapting to different oxygen concentrations under different environments [3,19]. Research into the adaptation of hypoxia is expected to lay the foundation for the treatment of hypoxia-related diseases [20]. The organism is a non-linear complex system of comprehensive regulation [3].…”

Section: Discussionmentioning

confidence: 99%

Lysophospholipid acyltransferase‐mediated formation of saturated glycerophospholipids maintained cell membrane integrity for hypoxic adaptation

Li,

Xia,

et al. 2024

The FEBS Journal

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Adaptation to hypoxia has attracted much public interest because of its clinical significance. However, hypoxic adaptation in the body is complicated and difficult to fully explore. To explore previously unknown conserved mechanisms and key proteins involved in hypoxic adaptation in different species, we first used a yeast model for mechanistic screening. Further multi‐omics analyses in multiple species including yeast, zebrafish and mice revealed that glycerophospholipid metabolism was significantly involved in hypoxic adaptation with up‐regulation of lysophospholipid acyltransferase (ALE1) in yeast, a key protein for the formation of dipalmitoyl phosphatidylcholine [DPPC (16:0/16:0)], which is a saturated phosphatidylcholine. Importantly, a mammalian homolog of ALE1, lysophosphatidylcholine acyltransferase 1 (LPCAT1), enhanced DPPC levels at the cell membrane and exhibited the same protective effect in mammalian cells under hypoxic conditions. DPPC supplementation effectively attenuated growth restriction, maintained cell membrane integrity and increased the expression of epidermal growth factor receptor under hypoxic conditions, but unsaturated phosphatidylcholine did not. In agreement with these findings, DPPC treatment could also repair hypoxic injury of intestinal mucosa in mice. Taken together, ALE1/LPCAT1‐mediated DPPC formation, a key pathway of glycerophospholipid metabolism, is crucial for cell viability under hypoxic conditions. Moreover, we found that ALE1 was also involved in glycolysis to maintain sufficient survival conditions for yeast. The present study offers a novel approach to understanding lipid metabolism under hypoxia and provides new insights into treating hypoxia‐related diseases.

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Section: Discussionmentioning

confidence: 99%

Lysophospholipid acyltransferase‐mediated formation of saturated glycerophospholipids maintained cell membrane integrity for hypoxic adaptation

Li,

Xia,

et al. 2024

The FEBS Journal

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“…Hypoxia triggers different responses, one of them being the stabilisation and import of the inducible factor α (HIF1α) into the nucleus. This factor induces the upregulation of miR-222-3p that, in turn, inhibits SRSF2 expression at a post-transcriptional level by binding its 3′ UTR, finally resulting in the aberrant expression of Vascular Endothelial Growth Factor A ( VEGFA ) isoforms in breast cancer [ 153 ]. A different mechanism has recently been described for SMC1A .…”

Section: Some Specific Examples Of Alternative Splicing In Driver Genesmentioning

confidence: 99%

The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes

Gimeno-Valiente,

López-Rodas,

Castillo

et al. 2024

Cancers

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Cancer driver genes are either oncogenes or tumour suppressor genes that are classically activated or inactivated, respectively, by driver mutations. Alternative splicing—which produces various mature mRNAs and, eventually, protein variants from a single gene—may also result in driving neoplastic transformation because of the different and often opposed functions of the variants of driver genes. The present review analyses the different alternative splicing events that result in driving neoplastic transformation, with an emphasis on their molecular mechanisms. To do this, we collected a list of 568 gene drivers of cancer and revised the literature to select those involved in the alternative splicing of other genes as well as those in which its pre-mRNA is subject to alternative splicing, with the result, in both cases, of producing an oncogenic isoform. Thirty-one genes fall into the first category, which includes splicing factors and components of the spliceosome and splicing regulators. In the second category, namely that comprising driver genes in which alternative splicing produces the oncogenic isoform, 168 genes were found. Then, we grouped them according to the molecular mechanisms responsible for alternative splicing yielding oncogenic isoforms, namely, mutations in cis splicing-determining elements, other causes involving non-mutated cis elements, changes in splicing factors, and epigenetic and chromatin-related changes. The data given in the present review substantiate the idea that aberrant splicing may regulate the activation of proto-oncogenes or inactivation of tumour suppressor genes and details on the mechanisms involved are given for more than 40 driver genes.

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Autophagy‐dependent alternative splicing of ribosomal protein S24 produces a more stable isoform that aids in hypoxic cell survival

Kerry,

Specker,

Mizzoni

et al. 2024

FEBS Letters

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Cells remodel splicing and translation machineries to mount specialized gene expression responses to stress. Here, we show that hypoxic human cells in 2D and 3D culture models increase the relative abundance of a longer mRNA variant of ribosomal protein S24 (RPS24L) compared to a shorter mRNA variant (RPS24S) by favoring the inclusion of a 22 bp cassette exon. Mechanistically, RPS24L and RPS24S are induced and repressed, respectively, by distinct pathways in hypoxia: RPS24L is induced in an autophagy‐dependent manner, while RPS24S is reduced by mTORC1 repression in a hypoxia‐inducible factor‐dependent manner. RPS24L produces a more stable protein isoform that aids in hypoxic cell survival and growth, which could be exploited by cancer cells in the tumor microenvironment.

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Hypoxia-induced loss of SRSF2-dependent DNA methylation promotes CTCF-mediated alternative splicing of VEGFA in breast cancer

Cited by 8 publications

References 57 publications

Lysophospholipid acyltransferase‐mediated formation of saturated glycerophospholipids maintained cell membrane integrity for hypoxic adaptation

Lysophospholipid acyltransferase‐mediated formation of saturated glycerophospholipids maintained cell membrane integrity for hypoxic adaptation

The Many Roads from Alternative Splicing to Cancer: Molecular Mechanisms Involving Driver Genes

Autophagy‐dependent alternative splicing of ribosomal protein S24 produces a more stable isoform that aids in hypoxic cell survival

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