Abbr. name AV ratio AV P-value Gsta3 glutathione S-, alpha 3 18.5 5.6E-04 Gpx2 glutathione peroxidase 2 13.1 3.7E-07 Nqo1 NAD(P)H dehydrogenase, quinone 1 12.2 3.5E-05 Srxn1 sulfiredoxin 1 homolog (S. cerevisiae) 4.9 1.0E-04 Gsta4 glutathione S-transferase, alpha 4 4.3 2.5E-05 Aldh3a1 aldehyde dehydrogenase family 3, subfamily A1 4.1 6.8E-04 Slc7a11 solute carrier family 7, member 11 2.9 1.2E-02 Abcc3 ATP-binding cassette, sub-family C, member 3 3.6 1.0E-04 Gstm1 glutathione S-transferase, mu 1 3.0 1.8E-04 Cbr3 carbonyl reductase 3 3.0 1.2E-04 Abcc4 ATP-binding cassette, sub-family C, member 4 2.8 1.7E-04 Gstm6 glutathione S-transferase, mu 6 2.7 1.0E-04 Gclm glutamate-cysteine , modifier subunit 2.1 5.0E-04 Akr1b8 aldo-keto reductase family 1, member B8 2.1 2.4E-03 Gsta2 glutathione S-transferase, alpha 2 (Yc2) 2.0 1.4E-03 Gclc glutamate-cysteine ligase, catalytic subunit 2.0 1.9E-03 Blvrb biliverdin reductase B (flavin reductase (NADPH)) 2.0 9.4E-04 Esd esterase D/formylglutathione 1.9 1.3E-04 Pgd phosphogluconate dehydrogenase 1.9 3.9E-04 Cbr1 carbonyl reductase 1 1.9 5.3E-04 Cat catalase 1.8 6.7E-04 Gss glutathione synthetase 1.8 1.3E-03 G6pd2 -6-phosphate dehydrogenase 2 1.8 1.4E-03 Txnrd1 thioredoxin reductase 1 1.6 9.1E-04 Gsto1 glutathione S-transferase omega 1 1.6 6.9E-03 Me1 malic 1, NADP(+)-dependent, cytosolic 1.6 5.0E-04 Gsr glutathione reductase 1 1.6 4.0E-04 G6pdx glucose-6-phosphate dehydrogenase X-linked 1.6 1.2E-03 Slc1a4 solute carrier family 1, member 4 1.6 6.4E-04 Pla2g7 phospholipase A2, group VII 1.5 4.6E-04

Supplementary Table S1: List of associated with detoxification with a fold change of 1.5 or higher and p-value lower than 0.05 analyzed by microarray analysis using skin of P2.5 K5cre-caNrf2 compared to control mice.

12 Abbr. Gene name AV ratio AV p-value Hk1 hexokinase 1 1.69 1.4E-03 Hk2 hexokinase 2 1.09 2.7E-01 Hk3 hexokinase 3 0.89 2.3E-01 Glucose-6-phosphate Gpi1 glucose phosphate isomerase 1 1.20 2.5E-02 Phosphofructokinase Pbkl phosphofructokinase, , B-type 1.14 8.3E-02 Pbkm phosphofructokinase, muscle 1.07 4.8E-01 Pbkp phosphofructokinase, platelet 1.06 5.3E-01 Fructose-1,6-bisphosphate aldolase Aldoa , fructose-bisphosphate 1.06 1.2E-01 Aldob , fructose-bisphosphate 1.08 1.5E-01 Aldoc , fructose-bisphosphate 0.99 8.7E-01 Triosephosphate isomerase Tpi1 triosephosphate isomerase 1 1.03 7.3E-01 Glyceraldehyde-3 phosphate dehydrogenase Gapdh glyceraldehyde-3 phosphate dehydrogenase 1.05 2.2E-01 Pgk1 phosphoglycerate kinase 1 1.06 3.5E-01 Pgam2 phosphoglycerate mutase 2 1.01 9.5E-01 Pgam5 phosphoglycerate mutase family member 5 0.99 8.4E-01 Eno1 enolase 1, alpha non-neuron 1.07 1.4E-01 Eno2 enolase 2, gamma neuronal 0.94 3.8E-01 Eno3 enolase 3, beta muscle 1.02 8.3E-01 Pklr pyruvate kinase liver and 1.05 5.8E-01 Pkir2 pyruvate kinase, muscle 1.14 7.9E-02 Ldha lactate dehydrogenase A 1.07 3.4E-01 Ldhb lactate dehydrogenase B 0.98 3.7E-01 Ldhd lactate dehydrogenase D 0.90 3.8E-01

Supplementary Table S2: Relative expression of genes encoding determined by microarray analysis using skin of P2.5 K5cre-caNrf2 and control mice.

13

Gene expression level Diff. No NQO1 SRXN1 G6PD PGD TKT IDH1 ME1 diagnosis

1 2.2 1.8 2.2 1.0 1.0 1.0 1.7 AK 2 1.7 4.0 1.5 1.2 1.5 1.3 1.0 AK/ MB 3 2.9 3.2 1.0 1.6 1.2 1.5 1.2 AK/ SCC 4 1.0 4.0 2.5 2.2 2.2 2.4 2.4 AK 5 4.8 2.1 0.7 0.9 1.1 0.9 0.7 AK/ MB 6 2.5 3.7 2.1 1.7 1.7 1.8 2.1 AK/ SCC 7* 1.6 6.6 2.1 1.7 1.1 1.9 1.4 AK 8* 2.1 3.5 2.5 1.8 1.4 2.0 1.7 AK 9 5.3 2.7 1.0 0.8 0.5 0.8 1.4 AK 10 0.8 2.9 1.5 N.A. 0.2 1.2 N.A. AK/ MB 11 0.5 2.2 0.8 N.A. 0.1 0.4 N.A. Atrophic AK 12 0.6 2.2 1.4 N.A. 0.1 0.7 N.A. Atrophic AK 13 6.6 2.7 3.0 2.1 1.5 2.9 2.0 AK

14 4.8 2.3 1.1 0.6 0.6 0.9 0.7 AK

Supplementary Table S3: Expression levels of NQO1, SRXN1, G6PDX, PGD, TKT,

IDH1 and ME1 relative to GAPDH as determined by qRT-PCR using RNA isolated from skin cancer precursor lesions and skin of healthy patients. Expression in normal skin was arbitrarily set to 1. The differential diagnosis is shown in the right panel.

Samples with increased expression of NQO1 and SXRN1 are highlighted in yellow, samples with additional upregulation of PPP genes are highlighted in red. Samples number 7 and 8 (indicated by *) are two different biopsies from the same patient. AK,

Actinic Keratosis; MB, Morbus Bowen; SCC, Squamous Cell Carcinoma. N.A., Not

Available.

14 Gene Forward primer Reverse primer Akr1b8 TGCTCTCAGCAAGATTTTGGCA TCTTTGACTTGGTTTGGGGGA Aurkb CAGAAGGAGAACGCCTACCC GAGAGCAAGCGCAGATGTC Birc3 ACGCAGCAATCGTGCATTTTG CCTATAACGAGGTCACTGACGG caNrf2 TGTTCCTTGTTCCCAAAAGC CCGGAATATTAATAGGGACGGTA Cbr1 TACCCGAGATGTCTGCAAGG CCTCTGTGATGGTCTCGCTT Cbr3 TCGACATTCAAGCTGAGGTGA CCTGCAGACTGCTGATGTTCA Ccnb1 GCGTGTGCCTGTGACAGTTA CCTAGCGTTTTTGCTTCCCTT Cyp1a1 TCGTGGAGCCTCATGTACCTGGT AAGCGCTTGTCCAGAGTGCCG Cyp1b1 CGCTTCATCGCATGGCC GGCGAGGACCACGGTTTCCG Ephx1 GAGTGGAGGAACTGCACACC GAAGCCAGGATGAGTTCCAG G6pdx AGCTACATAGGAATTACGGGCAA CACAGTGGACGACATCCGAAA Gapdh TCGTGGATCTGACGTGCCGCCTG CACCACCCTGTTGCTGTAGCCGTAT Gclc AACAAGAAACATCCGGCATC CGTAGCCTCGGTAAAATGGA Gclm TCCCATGCAGTGGAGAAGAT AGCTGTGCAACTCCAAGGAC Gsr GGCATGTCATCAAGCAGAAA TGTTGCATAGCCGTGGATAA Gss AGCTCGAAGAACTGGCAAAG AGCACTGGGTACTGGTGAGG Gsta2 ACTCCTCTGGAGCTGGATTG ATTGCAGCAACTGTGGTTCA Gsta3 TACTTTGATGGCAGGGGAAG GCACTTGCTGGAACATCAGA Gstm1 AGCTCATCATGCTCTGTTACAA CTGCAAACCATGGCCTCTT GCAGGACTGTTCAGTACCGTGCAA HPVE6 ACGGCCTCTCCCACAGCAATCT C Idh1 GCACATCCCCATCGTAATTCTTA ACAAGTCCCAGTTTGAAGCTC Il1b GGACAGAATATCAACCAACAAGTG TGCTGATGTACCAGTTGGGG Il6 CCGGAGAGGAGACTTCACAG TTCTGCAAGTGCATCATCGT

K10 ACGAAGAGCTGGCCTACCTA GCGTTCATTTCCACATTCAC K14 AACCACGAGGAGGAAATGG CCGGAGCTCAGAAATCTCAC Lor CACTCATCTTCCCTGGTGCT TCCACCAGAGGTCTTTCCAC Me1 GGAGCTCCAGGTCCTTAGAA ATCAGACATGAGCACGCTGT Nqo1 CTGGCCCATTCAGAGAAGAC GTCTGCAGCTTCCAGCTTCT Pgd CTGTCATGGGCCAGAACTTA CTCGTTGGCCAAGAAGTCA Rps29 GGTCACCAGCAGCTCTACG GTCCAACTTAATGAAGCCTATGTCC Taldo1 GCGAAGGAGAAAAGCAGTGT TTATCATCAACCTGGGAGGG Tnfa GACCCTCACACTCAGATCATCTTCT CCACTTGGTGGTTTGCTACGA Tnfaip3 CTGGATGTCAATCAACAATGGGA ACTAGGGTGTGAGTGTTTTCTGT Tkt CTGAAGGACACAGCCAATCG CAGGACAGCCATGATCTCG

Supplementary Table S4: Murine qRT-PCR primers.

18 Gene Forward primer Reverse primer GAPDH AAGGTCGGAGTCAACGGATT CTCCTGGAAGATGGTGATGG G6PDX GACATCCGCAAACAGAGTGA GGAGGCTGCATCATCGTACT IDH1 CACTACCGCATGTACCAGAAAGG TCTGGTCCAGGCAAAAATGG ME1 CTGCCTGTCATTCTGGATGT ACCTCTTACTCTTCTCTGCC NQO1 GTGATATTCCAGTTCCCCCTGC AAGCACTGCCTTCTTACTCCGG NRF2 AGGTTGCCCACATTCCCAAA AATGTCTGCGCCAAAAGCTG PGD ATATAGGGACACCACAAGACGG GCATGAGCGATGGGCCATA SRXN1 CAAGGTGCAGAGCCTCGT GATGGTCTCTCGCTGCAGTT TALDO1 GTCATCAACCTGGGAAGGAA CAACAAATGGGGAGATGAGG TKT GCTGAACCTGAGGAAGATCA TGTCGAAGTATTTGCCGGTG

Supplementary Table S5: Human qRT-PCR primers.

Antibody Host Dilution Source or publication Primary antibody

Adph guinea pig 1:200 Fitzgerald, Acton, MA CD3 rabbit 1:100 DAKO, Glostrup, Denmark kindly provided by Prof. P. Stoitzner, CD207 rat 1:100 University of Innsbruck, Austria cleaved caspase-3 rabbit 1:100 Cell Signaling, Danvers, MA Novus Biologicals, Cambridge, United γH2AX rabbit 1:300 Kingdom K10 rabbit 1:500 K14 rabbit 1:50000 Covance, Geneva, Switzerland Lor rabbit 1:250 Ly6G rat 1:100 BD Pharmingen, Allschwil, Switzerland NQO1 rabbit 1:100 Abcam, Cambridge, United Kingdom PCNA rabbit 1:1000 Santa Cruz Biotechnology, Santa Cruz, CA P-NRF2 (Ser40) rabbit 1:200 Abcam, Cambridge, United Kingdom Secondary antibody anti-rabbit biotin goat 1:500 Jackson ImmunoResearch, Suffolk, United anti-rabbit Cy3 goat 1:250 Kingdom anti-rat biotin rabbit 1:250 Vector Laboratories, Burlingame, CA anti-rat Cy3 donkey 1:200 Jackson ImmunoResearch anti-guinea pig Cy3 donkey 1:200

Supplementary Table S6: Antibodies used for immunofluorescence or immunohistochemistry staining.

19 Antibody Host Dilution Source or publication Primary antibody Akt rabbit 1:10000 p-Akt rabbit 1:2000 Cell Signaling Erk rabbit 1:1000 p-Erk rabbit 1:1000 G6pdx goat 1:1500 MyBioSource, San Diego, CA Pgd rabbit 1:1500 Abcam, Cambridge, UK Pten rabbit 1:1000 Cell Signaling Gapdh mouse 1:10000 HyTest, Turku, Finland Secondary antibody anti-goat AP rabbit 1:2000 Merck, Darmstadt, Germany anti-mouse AP goat 1:7500 Promega, Dübendorf, Switzerland anti-rabbit AP goat 1:7500

Supplementary Table S7: Antibodies used for western blotting.

20