Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects

Hashizume, Osamu; Ohnishi, Sakiko; Mito, Takayuki; Shimizu, Akinori; Ishikawa, Kaori; Nakada, Kazuto; Soda, Manabu; Mano, Hiroyuki; Togayachi, Sumie; Miyoshi, Hiroyuki; Okita, Keisuke; Hayashi, Jun Ichi

doi:10.1038/srep10434

Cited by 79 publications

(89 citation statements)

References 28 publications

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“…We found that HMEC derived from older women show increased basal traits, altered signal transduction in response to extracellular matrix proteins and evidence of reduced senescence following oncogene expression. We suggest that this is the result of epigenetic changes imposed on HMEC by an agerelated attenuation of the tissue microenvironment (Hashizume et al 2015).…”

Section: Ageing Luminal Cells Exhibit Basal-like Traitsmentioning

confidence: 88%

Microsphere cytometry to interrogate microenvironment-dependent cell signaling

et al. 2017

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2018Avhandling for graden philosophiae doctor (ph.d.)Dato for disputas: 06.04.18Trykk:Skipnes Kommunikasjon / Universitetet i Bergen Materialet i denne publikasjonen er omfattet av åndsverkslovens bestemmelser. Tittel:The effects of ageing on microenvironment-contextual epithelial cell signalling Rein Aasland, for valuable insight on academic writing, and for pointing out, as did James, when my words became self-indulgent fun and flowers. Mark LaBarge, for taking me into his lab, and letting me partake in that which concerns absolutely everyone: ageing. To Martha Stampfer for allowing me to poke around in her human cell resources biobank. To James Garbe for being an incredibly sympathetic guy with the most convenient knowledge up his sleeve.I would like to thank my mother Nina-Mamma for never curbing her enthusiasm for tiny biology when I brought home science homework, and my father Ulf for being genuinely impressed with pretty much everything I didincluding when I did it badly. I need to thank my boyfriend, Lars, for meticulous proofreading of the manuscript, and for continuously encouraging me to put my academic whims into writing. I want to point out that Iren Abrahamsen did substantial preliminary work for the microsphere cytometry method. I need to to thank my medical doctor office mates, Gry and Kjersti for valuable insights from the clinical realm where lab rats never go, to remind me who we're doing this for in the first place. Thanks to Sissel for being that steady rock in the corner stall of the lab where PhDs and postdocs fly by. I would like to thank the girls in the lab for taking up the fight against cancer cell Fråtse-Frida, and winning it. Finally, I would like to thank the Cancer Society, VilVite, CCBIO and Forskningsdagene for giving me trust, whether it was to develop flow cytometry protocols or popular science shows, or to interrogate the microenvironment I would like thank just anyone else in the lab and the general world who is interested and willing to contemplate big ideas such as the purpose of being. And at last, every single nerd: nerdy boys and nerdy girls. pathway activation levels in HMEC are attenuated with age, and that the diminished signaling magnitude in HMEC from ageing women correlated with reduced probability of activating oncogene-induced senescence.Our results suggest that attenuated cell signaling response may reduce the likelihood of activating oncogene induced senescence, for cells in ageing women. We hypothesize this is the result of age-related changes to the microenvironment that support age-emergent cellular phenotypes with increased cancer susceptibility.

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Section: Ageing Luminal Cells Exhibit Basal-like Traitsmentioning

confidence: 88%

Microsphere cytometry to interrogate microenvironment-dependent cell signaling

et al. 2017

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“…We screened 66 differentially expressed genes associated with CRC progression in 224 colon cancer tissues and 165 adjacent normal tissues from three GEO data sets and found that SHMT2 is important in CRC metabolism. SHMT2, which is responsible for the conversion of serine to glycine, supports cancer cell proliferation in various cancers (5,15,33). SHMT2 is upregulated in CRC and plays an important role in colorectal carcinogenesis (6,8).…”

Section: Discussionmentioning

confidence: 99%

“…By deep learning methods, we found that MET, CPM, SHMT2, GUCA2B, and SCN9A are significantly related to CRC progression. Among these genes, serine hydroxymethyltransferase 2 (SHMT2) plays a regulatory role in the conversion of serine to glycine, which controls cell proliferation (4,5).…”

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confidence: 99%

Loss of SHMT2 mediates 5-FU chemoresistance by inducing autophagy in colorectal cancer

Chen

Fan

Xiao

et al. 2019

Preprint

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Serine hydroxymethyltransferase 2 (SHMT2) plays a vital role in one-carbon metabolism and drives colorectal carcinogenesis. In our study, loss of SHMT2 induced 5-Fluorouracil (5-FU) chemoresistance and was associated with poor prognosis in colorectal cancer (CRC). To elucidate the possible mechanism and generate a strategy to sensitize CRC to 5-FU chemotherapy, we first identified the binding proteins of SHMT2 in cancer cells by mass spectrometry. We found that SHMT2 inhibited autophagy through binding cytoplasmic p53.In fact, SHMT2 prevented cytoplasmic p53 degradation by inhibiting the binding of p53 and HDM2. Under treatment with 5-FU, depletion of SHMT2 promoted autophagy and inhibited apoptosis. Autophagy inhibitors CQ decreased low SHMT2-induced 5-FU resistance in vitro and in vivo. Finally, we enhanced the lethality of 5-FU treatment to CRC cells through the autophagy inhibitor or knockdown of SHMT2 in patient-derived and CRC cell xenograft models. Our findings identified the low SHMT2-induced autophagy on 5-FU resistance in CRC. These results reveal SHMT2-p53 as a novel cancer therapeutic target to reduce chemotherapeutic drug resistance.

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“…Rather, the gene was downregulated in old cells. Rejuvenation reversed this repression and restored normal glycine levels in the mitochondria of rejuvenated fibroblasts [37] .…”

Section: Epigenetics and Aging: The Promise Of Rejuvenationmentioning

confidence: 93%

The Emerging View of Aging as a Reversible Epigenetic Process

López-León

Goya²

2017

Gerontology

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The achievement of animal cloning and subsequent development of cell reprogramming technology are having a profound impact on our view of the mechanisms of aging in complex organisms. The experimental evidence showing that an adult somatic nucleus implanted into an enucleated oocyte can give rise to a whole new individual strongly suggests that the integrity of the genome of an adult nucleus is fully preserved. Here, we will review recent experimental evidence showing that pluripotency gene-based cell reprogramming can erase the epigenetic marks of aging and rejuvenate cells from old individuals reversing most signs of aging and that when induced pluripotent stem cells are differentiated back to the cell type of origin, the rejuvenated cells share many of the features of wild-type counterparts from young donors. This evidence supports the idea that progressive epigenetic dysregulation may be the key driver of organismal aging and challenges the conventional view of aging as an irreversible process. The model of aging as an epigenetic process provides an elegant explanation of a number of age-related processes difficult to explain by conventional theories of aging.

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Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects

Cited by 79 publications

References 28 publications

Microsphere cytometry to interrogate microenvironment-dependent cell signaling

Microsphere cytometry to interrogate microenvironment-dependent cell signaling

Loss of SHMT2 mediates 5-FU chemoresistance by inducing autophagy in colorectal cancer

The Emerging View of Aging as a Reversible Epigenetic Process

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