Harri Itkonen

• Liang, Jing; Gondane, Aishwarya & Itkonen, Harri (2026). CDK12/13 Inhibition Induces DNA Hypomethylation and Sensitizes Cancer Cells to Compounds Targeting DNA-PK. Journal of Cellular and Molecular Medicine. ISSN 1582-1838. 30(16), s. 1–12. doi: 10.1111/jcmm.71323. Fulltekst i vitenarkiv
• Chatterjee, Joyeeta; Marin, Alessia; Yalala, Shivani & Itkonen, Harri (2026). Castration-resistant prostate cancer cells are addicted to the high activity of cyclin-dependent kinase 2. Molecular Oncology. ISSN 1574-7891. s. 1–19. doi: 10.1002/1878-0261.70319. Fulltekst i vitenarkiv
• Gondane, Aishwarya; Yalala, Shivani; Liang, Jing; Saira, Sonja & Itkonen, Harri (2026). Inactivation of CDK12 Enhances Mitochondrial Efficiency to Suppress DNA Damage. Journal of Cellular and Molecular Medicine. ISSN 1582-1838. 30(7). doi: 10.1111/jcmm.71101. Fulltekst i vitenarkiv
• Pallasaho, Satu; Gondane, Aishwarya; Kuivalainen, Anni; Girmay, Samuel; Moestue, Siver Andreas & Loda, Massimo [Vis alle 7 forfattere av denne artikkelen] (2022). Castration-resistant prostate cancer cells are dependent on the high activity of CDK7. Journal of Cancer Research and Clinical Oncology. ISSN 0171-5216. doi: 10.1007/s00432-022-04475-3. Fulltekst i vitenarkiv
• Barkovskaya, Anna; Seip, Kotryna; Prasmickaite, Lina; Mills, Ian Geoffrey; Moestue, Siver Andreas & Itkonen, Harri (2020). Inhibition of O-GlcNAc transferase activates tumor-suppressor gene expression in tamoxifen-resistant breast cancer cells. Scientific Reports. 10, s. 1–10. doi: 10.1038/s41598-020-74083-z. Fulltekst i vitenarkiv Vis sammendrag

  In this study, we probed the importance of O-GlcNAc transferase (OGT) activity for the survival of tamoxifen-sensitive (TamS) and tamoxifen-resistant (TamR) breast cancer cells. Tamoxifen is an antagonist of estrogen receptor (ERα), a transcription factor expressed in over 50% of breast cancers. ERα-positive breast cancers are successfully treated with tamoxifen; however, a significant number of patients develop tamoxifen-resistant disease. We show that in vitro development of tamoxifen-resistance is associated with increased sensitivity to the OGT small molecule inhibitor OSMI-1. Global transcriptome profiling revealed that TamS cells adapt to OSMI-1 treatment by increasing the expression of histone genes. This is known to mediate chromatin compaction. In contrast, TamR cells respond to OGT inhibition by activating the unfolded protein response and by significantly increasing ERRFI1 expression. ERRFI1 is an endogenous inhibitor of ERBB-signaling, which is a known driver of tamoxifen-resistance. We show that ERRFI1 is selectively downregulated in ERα-positive breast cancers and breast cancers driven by ERBB2. This likely occurs via promoter methylation. Finally, we show that increased ERRFI1 expression is associated with extended survival in patients with ERα-positive tumors (p = 9.2e−8). In summary, we show that tamoxifen-resistance is associated with sensitivity to OSMI-1, and propose that this is explained in part through an epigenetic activation of the tumor-suppressor ERRFI1 in response to OSMI-1 treatment.

• Itkonen, Harri; Poulose, Ninu; Steele, Rebecca E.; Martin, Sara E.S.; Levine, Zebulon G. & Duveau, Damien Y. [Vis alle 13 forfattere av denne artikkelen] (2020). Inhibition of O-GlcNAc transferase renders prostate cancer cells dependent on CDK9. Molecular Cancer Research. ISSN 1541-7786. 18(10), s. 1512–1521. doi: 10.1158/1541-7786.MCR-20-0339. Fulltekst i vitenarkiv
• Itkonen, Harri; Urbanucci, Alfonso; ES, Martin Sara; Khan, Aziz; Mathelier, Anthony & Thiede, Bernd [Vis alle 8 forfattere av denne artikkelen] (2019). High OGT activity is essential for MYC-driven proliferation of prostate cancer cells. Theranostics. 9(8), s. 2183–2197. doi: 10.7150/thno.30834. Fulltekst i vitenarkiv Vis sammendrag

  O-GlcNAc transferase (OGT) is overexpressed in aggressive prostate cancer. OGT modifies intra-cellular proteins via single sugar conjugation (O-GlcNAcylation) to alter their activity. We recently discovered the first fast-acting OGT inhibitor OSMI-2. Here, we probe the stability and function of the chromatin O-GlcNAc and identify transcription factors that coordinate with OGT to promote proliferation of prostate cancer cells. Methods: Chromatin immunoprecipitation (ChIP) coupled to sequencing (seq), formaldehyde-assisted isolation of regulatory elements, RNA-seq and reverse-phase protein arrays (RPPA) were used to study the importance of OGT for chromatin structure and transcription. Mass spectrometry, western blot, RT-qPCR, cell cycle analysis and viability assays were used to establish the role of OGT for MYC-related processes. Prostate cancer patient data profiled for both mRNA and protein levels were used to validate findings. Results: We show for the first time that OGT inhibition leads to a rapid loss of O-GlcNAc chromatin mark. O-GlcNAc ChIP-seq regions overlap with super-enhancers (SE) and MYC binding sites. OGT inhibition leads to down-regulation of SE-dependent genes. We establish the first O-GlcNAc chromatin consensus motif, which we use as a bait for mass spectrometry. By combining the proteomic data from oligonucleotide enrichment with O-GlcNAc and MYC ChIP-mass spectrometry, we identify host cell factor 1 (HCF-1) as an interaction partner of MYC. Inhibition of OGT disrupts this interaction and compromises MYC's ability to confer androgen-independent proliferation to prostate cancer cells. We show that OGT is required for MYC-mediated stabilization of mitotic proteins, including Cyclin B1, and/or the increased translation of their coding transcripts. This implies that increased expression of mRNA is not always required to achieve increased protein expression and confer aggressive phenotype. Indeed, high expression of Cyclin B1 protein has strong predictive value in prostate cancer patients (p=0.000014) while mRNA does not. Conclusions: OGT promotes SE-dependent gene expression. OGT activity is required for the interaction between MYC and HCF-1 and expression of MYC-regulated mitotic proteins. These features render OGT essential for the androgen-independent, MYC-driven proliferation of prostate cancer cells. Androgen-independency is the major mechanism of prostate cancer progression, and our study identifies OGT as an essential mediator in this process.

• Itkonen, Harri; Poulose, Ninu; Walker, Suzanne & Mills, Ian Geoffrey (2019). CDK9 Inhibition Induces a Metabolic Switch that Renders Prostate Cancer Cells Dependent on Fatty Acid Oxidation. Neoplasia. ISSN 1522-8002. 21(7), s. 713–720. doi: 10.1016/j.neo.2019.05.001. Fulltekst i vitenarkiv Vis sammendrag

  Cyclin-dependent kinase 9 (CDK9), a key regulator of RNA-polymerase II, is a candidate drug target for cancers driven by transcriptional deregulation. Here we report a multi-omics-profiling of prostate cancer cell responses to CDK9 inhibition to identify synthetic lethal interactions. These interactions were validated using live-cell imaging, mitochondrial flux-, viability- and cell death activation assays. We show that CDK9 inhibition induces acute metabolic stress in prostate cancer cells. This is manifested by a drastic down-regulation of mitochondrial oxidative phosphorylation, ATP depletion and induction of a rapid and sustained phosphorylation of AMP-activated protein kinase (AMPK), the key sensor of cellular energy homeostasis. We used metabolomics to demonstrate that inhibition of CDK9 leads to accumulation of acyl-carnitines, metabolic intermediates in fatty acid oxidation (FAO). Acyl-carnitines are produced by carnitine palmitoyltransferase enzymes 1 and 2 (CPT), and we used both genetic and pharmacological tools to show that inhibition of CPT-activity is synthetically lethal with CDK9 inhibition. To our knowledge this is the first report to show that CDK9 inhibition dramatically alters cancer cell metabolism.

• Barkovskaya, Anna; Seip, Kotryna; Hilmarsdòttir, Bylgja; Mælandsmo, Gunhild Mari; Moestue, Siver Andreas & Itkonen, Harri (2019). O-GlcNAc Transferase Inhibition Differentially Affects Breast Cancer Subtypes. Scientific Reports. 9(1), s. 1–11. doi: 10.1038/s41598-019-42153-6. Fulltekst i vitenarkiv Vis sammendrag

  Post-translational modification of intracellular proteins with a single N-acetylglucosamine sugar (O-GlcNAcylation) regulates signaling, proliferation, metabolism and protein stability. In breast cancer, expression of the enzyme that catalyzes O-GlcNAcylation – O-GlcNAc-transferase (OGT), and the extent of protein O-GlcNAcylation, are upregulated in tumor tissue, and correlate with cancer progression. Here we compare the significance of O-GlcNAcylation in a panel of breast cancer cells of different phenotypes. We find a greater dependency on OGT among triple-negative breast cancer (TNBC) cell lines, which respond to OGT inhibition by undergoing cell cycle arrest and apoptosis. Searching for the cause of this response, we evaluate the changes in the proteome that occur after OGT inhibition or knock-down, employing a reverse-phase protein array (RPPA). We identify transcriptional repressor - hairy and enhancer of split-1 (HES1) - as a mediator of the OGT inhibition response in the TNBC cells. Inhibition of OGT as well as the loss of HES1 results in potent cytotoxicity and apoptosis. The study raises a possibility of using OGT inhibition to potentiate DNA damage in the TNBC cells.

• Itkonen, Harri; Brown, Michael; Urbanucci, Alfonso; Tredwell, Gregory; Lau, Chung Ho & Barfeld, Stefan Jörg [Vis alle 21 forfattere av denne artikkelen] (2017). Lipid degradation promotes prostate cancer cell survival. OncoTarget. 8(24), s. 38264–38275. doi: 10.18632/oncotarget.16123. Fulltekst i vitenarkiv
• Urbanucci, Alfonso; Barfeld, Stefan Jörg; Kytölä, Ville; Itkonen, Harri; Coleman, Ilsa M. & Vodák, Daniel [Vis alle 34 forfattere av denne artikkelen] (2017). Androgen receptor deregulation drives bromodomain-mediated chromatin alterations in prostate cancer. Cell reports. 19(10), s. 2045–2059. doi: 10.1016/j.celrep.2017.05.049. Fulltekst i vitenarkiv Vis sammendrag

  Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

• Barfeld, Stefan Jörg; Urbanucci, Alfonso; Itkonen, Harri; Fazli, Ladan; Hicks, Jessica L & Thiede, Bernd [Vis alle 10 forfattere av denne artikkelen] (2017). c-Myc antagonises the transcriptional activity of the androgen receptor in prostate cancer affecting key gene networks. EBioMedicine. 18, s. 83–93. doi: 10.1016/j.ebiom.2017.04.006. Fulltekst i vitenarkiv Vis sammendrag

  Prostate cancer (PCa) is the most common non-cutaneous cancer in men. The androgen receptor (AR), a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signaling networks have been shown to be altered in patients and to influence AR activity. Amongst these, the oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies and elevated protein levels of c-Myc are commonly observed in PCa. Its impact on AR activity, however, remains elusive. In this study, we assessed the impact of c-Myc overexpression on AR activity and transcriptional output in a PCa cell line model and validated the antagonistic effect of c-MYC on AR-targets in patient samples. We found that c-Myc overexpression partially reprogrammed AR chromatin occupancy and was associated with altered histone marks distribution, most notably H3K4me1 and H3K27me3. We found c-Myc and the AR co-occupy a substantial number of binding sites and these exhibited enhancer-like characteristics. Interestingly, c-Myc overexpression antagonised clinically relevant AR target genes. Therefore, as an example, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 (alias PSA, prostate specific antigen), and Glycine N-Methyltransferase (GNMT), in patient samples. Our findings provide unbiased evidence that MYC overexpression deregulates the AR transcriptional program, which is thought to be a driving force in PCa.

• Fan, Qiong; Nørgaard, Rikke Christine; Bindesbøll, Christian; Lucas, Christin; Dalen, Knut Tomas & Babaie, Eshrat [Vis alle 10 forfattere av denne artikkelen] (2017). LXR? regulates hepatic ChREBP? activity and lipogenesis upon glucose, but not fructose feeding in mice. Nutrients. 9(7). doi: 10.3390/nu9070678. Fulltekst i vitenarkiv
• Itkonen, Harri; Gorad, Saurabh Sayajirao; Duveau, Damien Y.; Martin, Sara E.S.; Barkovskaya, Anna & Bathen, Tone Frost [Vis alle 8 forfattere av denne artikkelen] (2016). Inhibition of O-GlcNAc transferase activity reprograms prostate cancer cell metabolism. OncoTarget. 7(11), s. 12464–12476. doi: 10.18632/oncotarget.7039. Fulltekst i vitenarkiv Vis sammendrag

  Metabolic networks are highly connected and complex, but a single enzyme, O-GlcNAc transferase (OGT) can sense the availability of metabolites and also modify target proteins. We show that inhibition of OGT activity inhibits the proliferation of prostate cancer cells, leads to sustained loss of c-MYC and suppresses the expression of CDK1, elevated expression of which predicts prostate cancer recurrence (p=0.00179). Metabolic profiling revealed decreased glucose consumption and lactate production after OGT inhibition. This decreased glycolytic activity specifically sensitized prostate cancer cells, but not cells representing normal prostate epithelium, to inhibitors of oxidative phosphorylation (rotenone and metformin). Intra-cellular alanine was depleted upon OGT inhibitor treatment. OGT inhibitor increased the expression and activity of alanine aminotransferase (GPT2), an enzyme that can be targeted with a clinically approved drug, cycloserine. Simultaneous inhibition of OGT and GPT2 inhibited cell viability and growth rate, and additionally activated a cell death response. These combinatorial effects were predominantly seen in prostate cancer cells, but not in a cell-line derived from normal prostate epithelium. Combinatorial treatments were confirmed with two inhibitors against both OGT and GPT2. Taken together, here we report the reprogramming of energy metabolism upon inhibition of OGT activity, and identify synergistically lethal combinations that are prostate cancer cell specific.

• Itkonen, Harri; Engedal, Kim Nikolai; Babaie, Eshrat; Luhr, Morten; Guldvik, Ingrid Jenny & Minner, S [Vis alle 10 forfattere av denne artikkelen] (2015). UAP1 is overexpressed in prostate cancer and is protective against inhibitors of N-linked glycosylation. Oncogene. ISSN 0950-9232. 34(28), s. 3744–3750. doi: 10.1038/onc.2014.307. Fulltekst i vitenarkiv
• Barfeld, Stefan; Itkonen, Harri; Urbanucci, Alfonso & Mills, Ian Geoffrey (2014). Androgen-regulated metabolism and biosynthesis in prostate cancer. Endocrine-Related Cancer. ISSN 1351-0088. 21(4), s. T57–T66. doi: 10.1530/ERC-13-0515. Fulltekst i vitenarkiv
• Itkonen, Harri & Mills, Ian Geoffrey (2014). Studying N-linked glycosylation of receptor tyrosine kinases. Methods in molecular biology. ISSN 1064-3745. 1233, s. 103–109. doi: 10.1007/978-1-4939-1789-1_10. Fulltekst i vitenarkiv
• Itkonen, Harri & Mills, Ian Geoffrey (2013). N-Linked Glycosylation Supports Cross-Talk between Receptor Tyrosine Kinases and Androgen Receptor. PLOS ONE. 8(5). doi: 10.1371/journal.pone.0065016. Fulltekst i vitenarkiv Vis sammendrag

  Prostate cancer is the second most common cause of cancer-associated deaths in men and signalling via a transcription factor called androgen receptor (AR) is an important driver of the disease. Androgen treatment is known to affect the expression and activity of other oncogenes including receptor tyrosine kinases (RTKs). In this study we report that AR-positive prostate cancer cell-lines express 50% higher levels of enzymes in the hexosamine biosynthesis pathway (HBP) than AR-negative prostate cell-lines. HBP produces hexosamines that are used by endoplasmic reticulum and golgi enzymes to glycosylate proteins targeted to plasma-membrane and secretion. Inhibition of O-linked glycosylation by ST045849 or N-linked glycosylation with tunicamycin decreased cell viability by 20%. In addition, tunicamycin inhibited the androgen-induced expression of AR target genes KLK3 and CaMKK2 by 50%. RTKs have been shown to enhance AR activity and we used an antibody array to identify changes in the phosphorylation status of RTKs in response to androgen stimulation. Hormone treatment increased the activity of Insulin like Growth Factor 1-Receptor (IGF-1R) ten-fold and this was associated with a concomitant increase in the N-linked glycosylation of the receptor, analyzed by lectin enrichment experiments. Glycosylation is known to be important for the processing and stability of RTKs. Inhibition of N-linked glycosylation resulted in accumulation of IGF-1R pro-receptor with altered mobility as shown by immunoprecipitation. Confocal imaging revealed that androgen induced plasma-membrane localization of IGF-1R was blocked by tunicamycin. In conclusion we have established that the glycosylation of IGF-1R is necessary for the full activation of the receptor in response to androgen treatment and that perturbing this process can break the feedback loop between AR and IGF-1R activation in prostate cells. Achieving similar results selectively in a clinical setting will be an important challenge in the future.

• Itkonen, Harri; Minner, S; Guldvik, Ingrid Jenny; Sandmann, M; Tsourkalis, Maria & Berge, Viktor [Vis alle 9 forfattere av denne artikkelen] (2013). O-GlcNAc Transferase Integrates Metabolic Pathways to Regulate the Stability of c-MYC in Human Prostate Cancer Cells. Cancer Research. ISSN 0008-5472. 73. doi: 10.1158/0008-5472.CAN-13-0549. Fulltekst i vitenarkiv
• Itkonen, Harri & Mills, Ian Geoffrey (2012). Chromatin binding by the androgen receptor in prostate cancer. Molecular and Cellular Endocrinology. ISSN 0303-7207. 360(1-2), s. 44–51. doi: 10.1016/j.mce.2011.09.037. Fulltekst i vitenarkiv
• Paulo, Paula; Ribeiro, Franclim R; Santos, Joana; Mesquita, Diana; Almeida, Mafalda & Barros-Silva, Joao D. [Vis alle 14 forfattere av denne artikkelen] (2012). Molecular Subtyping of Primary Prostate Cancer Reveals Specific and Shared Target Genes of Different ETS Rearrangements. Neoplasia. ISSN 1522-8002. 14(7), s. 600–+. doi: 10.1593/neo.12600. Fulltekst i vitenarkiv

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• Barkovskaya, Anna; Hilmarsdòttir, Bylgja; Prasmickaite, Lina; Duveau, Damien Y.; Mills, Ian Geoffrey & Mælandsmo, Gunhild [Vis alle 8 forfattere av denne artikkelen] (2017). O-GlcNAc transferase inhibition in breast cancer cells. Fulltekst i vitenarkiv
• Barkovskaya, Anna; Prasmickaite, Lina; Duveau, Damien Y.; Mills, Ian Geoffrey; Mælandsmo, Gunhild & Moestue, Siver Andreas [Vis alle 7 forfattere av denne artikkelen] (2016). Inhibition of O-GlcNAc transferase in breast cancer cells. Fulltekst i vitenarkiv
• Itkonen, Harri; Kantelinen, Jukka; Vaara, Markku; Parkkinen, Sinikka; Schlott, Bernhard & Grosse, Frank [Vis alle 9 forfattere av denne artikkelen] (2016). Human DNA polymerase α interacts with mismatch repair proteins MSH2 and MSH6. FEBS Letters. ISSN 0014-5793. 590(23), s. 4233–4241. doi: 10.1002/1873-3468.12475. Fulltekst i vitenarkiv
• Barkovskaya, Anna; Prasmickaite, Lina; Duveau, Damien; Mills, Ian Geoffrey; Mælandsmo, Gunhild & Moestue, Siver Andreas [Vis alle 7 forfattere av denne artikkelen] (2016). Inhibition of O-GlcNAc transferase in breast cancer cells. Fulltekst i vitenarkiv
• Gorad, Saurabh Sayajirao; Itkonen, Harri; Moestue, Siver Andreas; Mills, Ian Geoffrey & Bathen, Tone Frost (2014). Metabolic and transcriptomic profiling of cancer cells treated with O-linked N-acetylglucosamine transferase inhibitor (STO45849). Fulltekst i vitenarkiv
• Itkonen, Harri & Mills, Ian Geoffrey (2012). Androgen Receptor Affects Glycosylation Pathways to Alter Growth Factor Receptor Signalling. European Journal of Cancer. ISSN 0959-8049. 48, s. S72–S73. Fulltekst i vitenarkiv

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