Metabolic reprogramming is an important feature of cancers that has been closely linked to post-translational protein modification (PTM). Lysine succinylation is a recently identified PTM involved in ...regulating protein functions, whereas its regulatory mechanism and possible roles in tumor progression remain unclear. Here, we show that OXCT1, an enzyme catalyzing ketone body oxidation, functions as a lysine succinyltransferase to contribute to tumor progression. Mechanistically, we find that OXCT1 functions as a succinyltransferase, with residue G424 essential for this activity. We also identified serine beta-lactamase-like protein (LACTB) as a main target of OXCT1-mediated succinylation. Extensive succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, ultimately leading to hepatocellular carcinoma (HCC) progression. In summary, this study establishes lysine succinyltransferase function of OXCT1 and highlights a link between HCC prognosis and LACTB K284 succinylation, suggesting a potentially valuable biomarker and therapeutic target for further development.
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•OXCT1 promotes lysine succinylation in HCC cells•OXCT1 functions as a lysine succinyltransferase•OXCT1 inhibits LACTB proteolytic activity via K284 succinylation•OXCT1 succinylation of LACTB promotes HCC progression
Ma and Sun et al. uncover that OXCT1, a conventional ketolysis enzyme, functions as a succinyltransferase and contributes to hepatocellular carcinoma (HCC) via succinylating and deactivating LACTB. Their findings establish a link between OXCT1-mediated LACTB succinylation and HCC prognosis, suggesting a potentially valuable biomarker and target for liver cancer therapy.
Metastasis is responsible for the majority of breast cancer-related deaths, however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic ...conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a, which facilitates breast cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis. Activation of HIF1 under hypoxia facilitated MBD2a production via repression of SRSF2-mediated alternative splicing. As a result, elevated MBD2a outcompeted MBD2c for binding to promoter CpG islands to activate expression of FZD1, thereby promoting epithelial-to-mesenchymal transition and metastasis. Strikingly, clinical data reveal significantly correlated expression of MBD2a and MBD2c with the invasiveness of malignancy, indicating opposing roles for MBD2 splicing variants in regulating human breast cancer metastasis. Collectively, our findings establish a novel link between MBD2 switching and tumor metastasis and provide a promising therapeutic strategy and predictive biomarkers for hypoxia-driven breast cancer metastasis. SIGNIFICANCE: This study defines the opposing roles and clinical relevance of MBD2a and MBD2c, two MBD2 alternative splicing products, in hypoxia-driven breast cancer metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/5/1265/F1.large.jpg.
DIS3-like 3'-5' exoribonuclease 2 (DIS3L2) degrades aberrant RNAs, however, its function in tumorigenesis remains largely unexplored. Here, aberrant DIS3L2 expression promoted human hepatocellular ...carcinoma (HCC) progression via heterogeneous nuclear ribonucleoproteins (hnRNP) U-mediated alternative splicing. DIS3L2 directly interacted with hnRNP U through its cold-shock domains and promoted inclusion of exon 3b during splicing of pre-Rac1 independent of its exonuclease activity, yielding an oncogenic splicing variant, Rac1b, which is known to stimulate cellular transformation and tumorigenesis. DIS3L2 regulated alternative splicing by recruiting hnRNP U to pre-Rac1. Rac1b was critical for DIS3L2 promotion of liver cancer development both
and
. Importantly, DIS3L2 and Rac1b expression highly correlated with HCC progression and patient survival. Taken together, our findings uncover an oncogenic role of DIS3L2, in which it promotes liver cancer progression through a previously unappreciated mechanism of regulating hnRNP U-mediated alterative splicing. SIGNIFICANCE: These findings establish the role and mechanism of the 3'-5' exoribonuclease DIS3L2 in hepatocellular carcinoma carcinogenesis.
Phosphoglycerate dehydrogenase (PHGDH) is a key serine biosynthesis enzyme whose aberrant expression promotes various types of tumors. Recently, PHGDH has been found to have some non‐canonical ...functions beyond serine biosynthesis, but its specific mechanisms in tumorigenesis remain unclear. Here, we show that PHGDH localizes to the inner mitochondrial membrane and promotes the translation of mitochondrial DNA (mtDNA)‐encoded proteins in liver cancer cells. Mechanistically, we demonstrate that mitochondrial PHGDH directly interacts with adenine nucleotide translocase 2 (ANT2) and then recruits mitochondrial elongation factor G2 (mtEFG2) to promote mitochondrial ribosome recycling efficiency, thereby promoting mtDNA‐encoded protein expression and subsequent mitochondrial respiration. Moreover, we show that treatment with a mitochondrial translation inhibitor or depletion of mtEFG2 diminishes PHGDH‐mediated tumor growth. Collectively, our findings uncover a previously unappreciated function of PHGDH in tumorigenesis acting via promotion of mitochondrial translation and bioenergetics.
Synopsis
This study reports a non‐catalytic tumorigenic role for serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH) in enhancing mitochondrial translation and respiratory metabolism in cancer cells, suggesting a new target for tumour progression.
PHGDH localizes to the inner mitochondrial membrane in human liver cancer cells and patient tissues.
PHGDH promotes translation of mtDNA‐encoded ETC proteins in catalytic activity‐independent manner.
PHGDH forms a complex with mitochondrial translation factors ANT2 and mtEFG2, enhancing mtRRF interaction and mitoribosome recycling.
PHGDH increases tumour growth in mice translation‐dependently by elevating respiratory metabolism.
A novel non‐catalytic function of serine biosynthesis enzyme PHGDH spurs cancer cell protein translation for enhanced bioenergetics.
Lin28 plays an important role in promoting tumor development, whereas its exact functions and underlying mechanisms are largely unknown. Here, we show that both human homologs of Lin28 accelerate de ...novo fatty acid synthesis and promote the conversion from saturated to unsaturated fatty acids via the regulation of SREBP‐1. By directly binding to the mRNAs of both SREBP‐1 and SCAP, Lin28A/B enhance the translation and maturation of SREBP‐1, and protect cancer cells from lipotoxicity. Lin28A/B‐stimulated tumor growth is abrogated by SREBP‐1 inhibition and by the impairment of the RNA binding properties of Lin28A/B, respectively. Collectively, our findings uncover that post‐transcriptional regulation by Lin28A/B enhances de novo fatty acid synthesis and metabolic conversion of saturated and unsaturated fatty acids via SREBP‐1, which is critical for cancer progression.
Synopsis
Post‐transcriptional regulation by Lin28A and Lin28B enhances de novo fatty acid synthesis and metabolic conversion of saturated and unsaturated fatty acids via SREBP‐1, thereby promoting tumor progression.
Lin28A and Lin28B promote de novo fatty acid synthesis.
Lin28A/B enhance SREBP‐1 translation and maturation by binding SREBP‐1 and SCAP mRNAs.
Lin28A/B protect cancer cells from ER stress.
SREBP‐1 is critical for Lin28A/B‐mediated tumor proliferation.
Post‐transcriptional regulation by Lin28A and Lin28B enhances de novo fatty acid synthesis and metabolic conversion of saturated and unsaturated fatty acids via SREBP‐1, thereby promoting tumor progression.
Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor ...progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H
mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.
The MYC oncoprotein activates and represses gene expression in a transcription‐dependent or transcription‐independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. ...We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down‐regulating N6‐methyladenosine (m6A) preferentially in transcripts of a subset of MYC‐repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m6A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC‐regulated m6A controls the translation of MRG mRNA via the specific m6A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC‐deregulated B‐cell lymphomas, both in vitro and in vivo. Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m6A modifications in selected MRG transcripts promotes cancer progression.
SYNOPSIS
MYC suppresses gene expression by indirectly altering m6A modifications in transcripts of MYC‐repressed genes via ALKBH5 to promote cancer progression.
MYC indirectly down‐regulates m6A levels in mRNA and inhibits protein expression of selected MRG transcripts.
MYC transcriptionally activates the m6A demethylases ALKBH5 and FTO.
ALKBH5 removes m6A and YTHDF3 binds m6A‐modified mRNAs to regulate the translation of SPI1/PHF12.
The MYC‐ALKBH5‐m6A‐SPI1/PHF12 axis is critical for cancer progression.
MYC suppresses gene expression by indirectly altering m6A modifications in transcripts of MYC‐repressed genes via ALKBH5 to promote cancer progression.
α-Enolase 1 (ENO1) is a critical glycolytic enzyme whose aberrant expression drives the pathogenesis of various cancers. ENO1 has been indicated as having additional roles beyond its conventional ...metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we show that ENO1 suppresses iron regulatory protein 1 (IRP1) expression to regulate iron homeostasis and survival of hepatocellular carcinoma (HCC) cells. Mechanistically, we demonstrate that ENO1, as an RNA-binding protein, recruits CNOT6 to accelerate the messenger RNA decay of IRP1 in cancer cells, leading to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis. Moreover, through in vitro and in vivo experiments and clinical sample analysis, we identified IRP1 and Mfrn1 as tumor suppressors by inducing ferroptosis in HCC cells. Taken together, this study establishes an important role for the ENO1-IRP1-Mfrn1 pathway in the pathogenesis of HCC and reveals a previously unknown connection between this pathway and ferroptosis, suggesting a potential innovative cancer therapy.
•Cancer cells utilize a variety of nutrients for survival under hypoxia.•Hypoxia promotes selective gene expression and protein translocation in cancer cells.•Hypoxia regulates the function of immune ...cells directly.•The reciprocal regulation of cancer cells and surrounding immune cells under hypoxia.
Cancer cells are frequently surrounded by hypoxic microenvironment and, to survive, they have evolved multiple adaptations. One of the hallmark adaptations for cancer cells is the rewired metabolism, in which hypoxia plays important roles. Besides rewired metabolism in cancer cells, much progresses has emerged in hypoxia-regulated immune cells and immune responses as well. Here, we will review the recent progress in the field of rewired cancer metabolism and tumor immunity regulated by hypoxic microenvironment.
The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. ...We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m
A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m
A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC-regulated m
A controls the translation of MRG mRNA via the specific m
A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC-deregulated B-cell lymphomas, both in vitro and in vivo. Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m
A modifications in selected MRG transcripts promotes cancer progression.
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