Browsing by Subject "MYC"

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  • Passador-Santos, F.; Gronroos, M.; Irish, J.; Gilbert, R.; Gullane, P.; Perez-Ordonez, B.; Makitie, A.; Leivo, I. (2016)
    Myoepithelial carcinoma (MCA) is a rare malignancy of salivary glands that was included in the WHO Classification of Head and Neck Tumors in 1991. MCA has shown a broad spectrum of clinical outcomes, but attempts to identify prognostic markers for this malignancy have not resulted in significant progress. Conventional histopathological characteristics such as tumour grade, nuclear atypia, mitotic index and cell proliferation have failed to predict the outcome of MCA. In this study, we reviewed the histopathology of 19 cases of MCA focusing on nuclear atypia, mitotic count, tumour necrosis, nerve and vascular invasion and occurrence of a pre-existing pleomorphic adenoma in connection to the MCA. Histopathological characteristics and clinical information were correlated with the immunohistochemical expression of cell cycle proteins including c-Myc, p21, Cdk4 and Cyclin D3. The proportion of tumour cells immunoreactive for these markers and their intensity of staining were correlated with clinical information using logistic regression, Kaplan-Meier and Cox regression. Using logistic regression analysis, cytoplasmic c-Myc expression was associated with the occurrence of metastases (P = 0.019), but limitations of semi-quantitation of immunostaining and the limited number of cases preclude definitive conclusions. Our data show that the occurrence of tumour necrosis predicts poor disease-free survival in MCA (P = 0.035).
  • Yanku, Yifat; Bitman-Lotan, Eliya; Zohar, Yaniv; Kurant, Estee; Zielke, Norman; Eilers, Martin; Orian, Amir (2018)
    The HECT-type ubiquitin ligase HECT, UBA and WWE Domain Containing 1, (HUWE1) regulates key cancer-related pathways, including the Myc oncogene. It affects cell proliferation, stress and immune signaling, mitochondria homeostasis, and cell death. HUWE1 is evolutionarily conserved from Caenorhabditis elegance to Drosophila melanogaster and Humans. Here, we report that the Drosophila ortholog, dHUWE1 (CG8184), is an essential gene whose loss results in embryonic lethality and whose tissue-specific disruption establishes its regulatory role in larval salivary gland development. dHUWE1 is essential for endoreplication of salivary gland cells and its knockdown results in the inability of these cells to replicate DNA. Remarkably, dHUWE1 is a survival factor that prevents premature activation of JNK signaling, thus preventing the disintegration of the salivary gland, which occurs physiologically during pupal stages. This function of dHUWE1 is general, as its inhibitory effect is observed also during eye development and at the organismal level. Epistatic studies revealed that the loss of dHUWE1 is compensated by dMyc proeitn expression or the loss of dmP53. dHUWE1 is therefore a conserved survival factor that regulates organ formation during Drosophila development.
  • Sahu, Biswajyoti; Pihlajamaa, Päivi; Zhang, Kaiyang; Palin, Kimmo; Ahonen, Saija; Cervera, Alejandra; Ristimäki, Ari; Aaltonen, Lauri A.; Hautaniemi, Sampsa; Taipale, Jussi (2021)
    Cancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis.
  • Barkovskaya, Anna; Seip, Kotryna; Prasmickaite, Lina; Mills, Ian G; Moestue, Siver A; Itkonen, Harri M. (2020)
    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 (ERa), a transcription factor expressed in over 50% of breast cancers. ERa-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 tamoxifenresistance 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 ERa-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 ERa-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.
  • Savelius, Mariel (Helsingin yliopisto, 2020)
    Breast cancer remains as the leading cause of cancer deaths among women. Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes and lacks targetable receptors, consequently, cannot be treated with current hormone of anti-HER2 targeting therapies. Thus, there is a need for discovering novel and well-tolerated therapies. MYC is a proto-oncogene and a transcription factor, that is frequently amplified and overexpressed in breast cancers. MYC is involved in many cellular processes promoting cell proliferation, however, overexpression of MYC can also sensitize cells to replicative stress and apoptotic cell death. In our previous studies we have shown that pharmacological activation of AMPK, a cellular energy sensor, synergises with Bcl-2 family inhibitors, such as navitoclax and venetoclax, and activates MYC-dependent apoptosis in breast cancer cell lines, transgenic mouse models of MYC-dependent mammary tumorigenesis and in MYC-high patient-derived explant cultures (PDECs). In subsequent study we observed, that indirect AMPK activator metformin alone inhibited tumor growth in vivo, but did not induce apoptosis in mouse tumors or in PDECs. Metformin, a type II diabetes mellitus drug, has shown anti-cancer effects in some population studies and is under investigation for a cancer therapies, however the whole mechanism of action in cancer is still not well-known. To elucidate metformin’s effects on MYC overexpressing triple-negative breast cancer cells, I will present, that metformin has anti-proliferative effects and show that long term metformin treatment induces senescence biomarkers in MYC-high TNBC breast cancer cell lines. To study metformin's short and long-term anti-proliferative activity, cell proliferation during and after drug treatment was investigated, which showed, that metformin’s effects do not seem to persist long after drug withdrawal. In conclusion, the key observation of this thesis was, that metformin does inhibit the proliferation of MYC overexpressing cancer cells and presents a senescence phenotype that possibly can be exploited to find new targeted therapies for triple-negative breast cancer patients.
  • Meriranta, Leo (Helsingin yliopisto, 2019)
    Concomitant deregulation of MYC and BCL2, whether at the genomic or protein level, comprises a clinically significant poorly characterized biological high-risk feature in diffuse large B-cell lymphoma (DLBCL). To interrogate these lymphomas, we comprehensively characterized genomic alterations and protein expression of BCL2, BCL6 and MYC in the context of comprehensive mutational, transcriptomic and clinical data in 181 patients with primary DLBCL. While the structural variations of BCL2 were subtype-specific and specifically increased BCL2 expression, molecular dissection of MYC deregulation revealed associations with other lymphoma drivers, of which we highlight concurrent TP53 alterations. Double protein expression (DPE) arose from heterogeneous molecular backgrounds in a subtype-dependent manner. In GCB DLBCL, concurrent alterations of MYC and BCL2 loci gave rise to the majority of DPE DLBCLs, whereas in the ABC DLBCLs, concurrent alterations were infrequent. Clinically, DPE DLBCL defined a prognostic entity, which was independent of International Prognostic Index (IPI) and cell-of-origin, and together with TP53 alterations had synergistic dismal impact on survival. Importantly, BCL6 translocations identified non-GCB lymphomas with favorable BN2/C1 -like outcomes independent of IPI and concurrent DPE status. Our findings elucidate the pathogenesis and biological determinants of high-risk DLBCL and reveal subtype-specific and clinically feasible predictors of subtype and outcome.
  • Haikala, Heidi M.; Klefstrom, Juha; Eilers, Martin; Wiese, Katrin E. (2016)
    Apoptosis caused by deregulated MYC expression is a prototype example of intrinsic tumor suppression. However, it is still unclear how supraphysiological MYC expression levels engage specific sets of target genes to promote apoptosis. Recently, we demonstrated that repression of SRF target genes by MYC/MIZ1 complexes limits AKT-dependent survival signaling and contributes to apoptosis induction. Here we report that supraphysiological levels of MYC repress gene sets that include markers of basal-like breast cancer cells, but not luminal cancer cells, in a MIZ1-dependent manner. Furthermore, repressed genes are part of a conserved gene signature characterizing the basal subpopulation of both murine and human mammary gland. These repressed genes play a role in epithelium and mammary gland development and overlap with genes mediating cell adhesion and extracellular matrix organization. Strikingly, acute activation of oncogenic MYC in basal mammary epithelial cells is sufficient to induce luminal cell identity markers. We propose that supraphysiological MYC expression impacts on mammary epithelial cell identity by repressing lineage-specific target genes. Such abrupt cell identity switch could interfere with adhesion-dependent survival signaling and thus promote apoptosis in pre-malignant epithelial tissue.
  • Gondane, Aishwarya; Girmay, Samuel; Helevä, Alma; Pallasaho, Satu; Loda, Massimo; Itkonen, Harri M. (2022)
    Background: Transcription, metabolism and DNA damage response are tightly regulated to preserve the genomic integrity, and O-GlcNAc transferase (OGT) is positioned to connect the three. Prostate cancer is the most common cancer in men, and androgen-ablation therapy halts disease progression. However, a significant number of prostate cancer patients develop resistance against anti-androgens, and this incurable disease is termed castration-resistant prostate cancer (CRPC). We have shown that combined inhibition of OGT and the transcription elongation kinase CDK9 induce CRPC-selective anti-proliferative effects. Here, we explain the functional basis for these combinatorial effects. Methods: We used comprehensive mass spectrometry profiling of short-term CDK9 inhibitor effects on O-GlcNAcylated proteins in an isogenic cell line system that models transition from PC to CRPC. In addition, we used both ChIP-seq and RNA-seq profiling, and pulldown experiments in multiple CRPC models. Finally, we validated our findings in prostate cancer patient samples. Results: Inhibition of CDK9 results in an OGT-dependent remodeling of the proteome in prostate cancer cells. More specifically, the activity of the DNA damage repair protein MRE11 is regulated in response to CDK9 inhibition in an OGT-dependent manner. MRE11 is enriched at the O-GlcNAc-marked loci. CDK9 inhibition does not decrease the expression of mRNAs whose genes are bound by both O-GlcNAc and MRE11. Combined inhibition of CDK9 and OGT or MRE11 further decreases RNA polymerase II activity, induces DNA damage signaling, and blocks the survival of prostate cancer cells. These effects are seen in CRPC cells but not in normal prostate cells. Mechanistically, OGT activity is required for MRE11 chromatin-loading in cells treated with CDK9 inhibitor. Finally, we show that MRE11 and O-GlcNAc are enriched at the prostate cancer-specific small nucleotide polymorphic sites, and the loss of MRE11 activity results in a hyper-mutator phenotype in patient tumors. Conclusions: Both OGT and MRE11 are essential for the repair of CDK9 inhibitor-induced DNA damage. Our study raises the possibility of targeting CDK9 to elicit DNA damage in CRPC setting as an adjuvant to other treatments.
  • Liu, Ying; Mattila, Jaakko; Hietakangas, Ville (2020)
    Insulin/insulin-like growth factor signaling (IIS) is a conserved mechanism to regulate animal physiology in response to nutrition. IIS activity controls gene expression, but only a subset of transcriptional regulators (TRs) targeted by the IIS pathway is currently known. Here we report the results of an unbiased screen forDrosophilaTRs phosphorylated in an IIS-dependent manner. To conduct the screen, we built a library of 857 V5/Strep-tagged TRs under the control of Copper-inducible metallothionein promoter (pMt). The insulin-induced phosphorylation changes were detected by using Phos-tag SDS-PAGE and Western blotting. Eight proteins were found to display increased phosphorylation after acute insulin treatment. In each case, the insulin-induced phosphorylation was abrogated by mTORC1 inhibitor rapamycin. The hits included two components of the NURF complex (NURF38 and NURF55), bHLHZip transcription factor Max, as well as theDrosophilaortholog of human proliferation-associated 2G4 (dPA2G4). Subsequent experiments revealed that the expression of thedPA2G4gene was promoted by the mTOR pathway, likely through transcription factor Myc. Furthermore, NURF38 was found to be necessary for growth in larvae, consistent with the role of IIS/mTOR pathway in growth control.