Metformin mediated reversal of epithelial to mesenchymal transition is triggered by epigenetic changes in E-cadherin promoter

Banerjee, Poulomi; Surendran, Harshini; Chowdhury, Debabani Roy; Prabhakar, Karthik; Pal, Rajarshi

doi:10.1007/s00109-016-1455-7

Cited by 43 publications

(42 citation statements)

References 37 publications

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“…Re cent at ten tion on the biguanide based an ti cancer ther a pies has high lighted the in volve ment of AMPK in pe cu liar be hav iours of can cer cells like the ca pac ity to un dergo EMT pro gram and to metas ta size. As met formin showed po tent an ti cancer ef fects by de plet ing ATP pro duc tion through its mi to chon dr ial in hibitory ca pac ity [228], con se quent AMPK ac ti va tion was found to be ef fec tive in me di at ing meta bolic cri sis and cy to toxic ef fect not only on pro lif er at ing cells but also on mi grat ing cells, through re pres sion of EMT path ways [229]. Other stud ies have shown that AMPK con tributes to cell mi gra tion [230,231].…”

Section: Metabolic Contribution To Cancer Metastasismentioning

confidence: 98%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

178

139

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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Section: Metabolic Contribution To Cancer Metastasismentioning

confidence: 98%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

178

139

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“…How this broad reprogramming of membrane traffic by AMPK contributes to some of the established cell and tissue outcomes of AMPK is an important area of investigation with many open questions. For example, many studies have revealed that AMPK regulates epithelial‐mesenchymal transition (EMT), a cellular differentiation program that is important for development and tissue repair and that is also critical to progression of diseases such as cancer and kidney disease . Importantly, EMT elicits and requires broad remodeling of membrane traffic .…”

Section: Control Of Endocytic Membrane Traffic By Ampkmentioning

confidence: 99%

Energetic adaptations: Metabolic control of endocytic membrane traffic

Rahmani

Defferrari

Wakarchuk

et al. 2019

Traffic

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Endocytic membrane traffic controls the access of myriad cell surface proteins to the extracellular milieu, and thus gates nutrient uptake, ion homeostasis, signaling, adhesion and migration. Coordination of the regulation of endocytic membrane traffic with a cell's metabolic needs represents an important facet of maintenance of homeostasis under variable conditions of nutrient availability and metabolic demand. Many studies have revealed intimate regulation of endocytic membrane traffic by metabolic cues, from the specific control of certain receptors or transporters, to broader adaptation or remodeling of the endocytic membrane network. We examine how metabolic sensors such as AMP‐activated protein kinase, mechanistic target of rapamycin complex 1 and hypoxia inducible factor 1 determine sufficiency of various metabolites, and in turn modulate cellular functions that includes control of endocytic membrane traffic. We also examine how certain metabolites can directly control endocytic traffic proteins, such as the regulation of specific protein glycosylation by limiting levels of uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) produced by the hexosamine biosynthetic pathway. From these ideas emerge a growing appreciation that endocytic membrane traffic is orchestrated by many intrinsic signals derived from cell metabolism, allowing alignment of the functions of cell surface proteins with cellular metabolic requirements. Endocytic membrane traffic determines how cells interact with their environment, thus defining many aspects of nutrient uptake and energy consumption. We examine how intrinsic signals that reflect metabolic status of a cell regulate endocytic traffic of specific proteins, and, in some cases, exert broad control of endocytic membrane traffic phenomena. Hence, endocytic traffic is versatile and adaptable and can be modulated to meet the changing metabolic requirements of a cell.

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“…In particular, as these studies were conducted using cancer cells to investigate the potential anticancer activity of metformin, changes in histone methylation as a result of metformin treatment may lead to increased expression of tumour suppressor genes. For example, Banerjee et al reported that metformin treatment decreased H3K9 and H3K27 methylation, and it increased H3K4 methylation in breast cancer cells as well, both globally and specifically at the promoter of the tumour suppressor gene E‐cadherin . These modifications may be a result of inhibition of HMTs; reductions in mRNA and protein expression of SUV39H1 and MMSET, HMTs that influence the methylation of H3K9 and H3K27, respectively, have been reported in metformin‐treated prostate cancer cells.…”

Section: Metforminmentioning

confidence: 99%

“…Reduced DNA methylation with metformin treatment has been reported at the insulin gene promoter in a β cell line cultured using high glucose concentrations and at the promoter of the tumour suppressor gene E‐cadherin in both cancer cell lines and white blood cells from diabetic patients, leading to increased expression of the respective genes. These results thus implicate DNA demethylation in the antidiabetic and potential anti‐cancer actions of metformin.…”

Section: Metforminmentioning

confidence: 99%

“…This may account for some of the disparate results. For example, studies reporting DNA hypomethylation with metformin were conducted in diabetic patients using therapeutic doses of metformin or micromolar doses of 500 μM or 20 μM . Conversely, studies associating metformin with DNA hypermethylation used suprapharmacological concentrations between 1 and 10 mM .…”

Section: Limitations Of Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic effects of metformin: From molecular mechanisms to clinical implications

Bridgeman

Ellison

Melton

et al. 2018

Diabetes Obesity Metabolism

152

100

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There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP-activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), usually resulting in their inhibition; however, HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, to increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and, potentially, may protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists concerning the overall effect of metformin on the epigenome, on gene expression, and on the subsequent effect on the health of metformin users.

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Metformin mediated reversal of epithelial to mesenchymal transition is triggered by epigenetic changes in E-cadherin promoter

Cited by 43 publications

References 37 publications

Cancer metabolism in space and time: Beyond the Warburg effect

Cancer metabolism in space and time: Beyond the Warburg effect

Energetic adaptations: Metabolic control of endocytic membrane traffic

Epigenetic effects of metformin: From molecular mechanisms to clinical implications

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