The Dual Roles of MYC in Genomic Instability and Cancer Chemoresistance

Kumari, Anjana; Folk, Watson P.; Sakamuro, Daitoku

doi:10.3390/genes8060158

Cited by 45 publications

(74 citation statements)

References 154 publications

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“…Chemoresistance is achieved by diverse means, such as through membrane proteins that modulate absorption and excretion of many compounds to maintain their concentration at non-toxic levels. Some of these proteins are, indeed, targets of cMYC 51 and miR-27a. 52 Resistance can also be elicited by interfering with various steps in nucleic acid metabolism through inhibition/activation of key target enzymes.…”

Section: Discussionmentioning

confidence: 99%

miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer

et al. 2020

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BACKGROUND: Metabolic reprogramming towards aerobic glycolysis in cancer supports unrestricted cell proliferation, survival and chemoresistance. The molecular bases of these processes are still undefined. Recent reports suggest crucial roles for microRNAs. Here, we provide new evidence of the implication of miR-27a in modulating colorectal cancer (CRC) metabolism and chemoresistance. METHODS: A survey of miR-27a expression profile in TCGA-COAD dataset revealed that miR-27a-overexpressing CRCs are enriched in gene signatures of mitochondrial dysfunction, deregulated oxidative phosphorylation, mTOR activation and reduced chemosensitivity. The same pathways were analysed in cell lines in which we modified miR-27a levels. The response to chemotherapy was investigated in an independent cohort and cell lines. RESULTS: miR-27a upregulation in vitro associated with impaired oxidative phosphorylation, overall mitochondrial activities and slight influence on glycolysis. miR-27a hampered AMPK, enhanced mTOR signalling and acted in concert with oncogenes and tumour cell metabolic regulators to force an aerobic glycolytic metabolism supporting biomass production, unrestricted growth and chemoresistance. This latter association was confirmed in our cohort of patients and cell lines. CONCLUSIONS: We disclose an unprecedented role for miR-27a as a master regulator of cancer metabolism reprogramming that impinges on CRC response to chemotherapy, underscoring its theragnostic properties.

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Section: Discussionmentioning

confidence: 99%

miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer

et al. 2020

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“…This gene is one of the most potent cellular protooncogenes and encodes c-Myc protein. c-Myc is a transcription factor that binds to DNA (via helix-loophelix and leucine zipper domains) and regulates the expression of the genes involved in many cellular functions, including cell proliferation and DNA replication [30][31][32][33] . c-Myc can heterodimerize with other transcription factors like Max to increase the number of the target genes.…”

Section: C-mycmentioning

confidence: 99%

“…It is estimated that c-Myc is involved in the expression of more than 15% of cellular genes supporting the role of this protein in many cellular functions [33] . c-Myc binds to the enhancer box sequences on DNA, and by recruiting important proteins like histone acetyltransferases, it regulates gene expression [32,33] . c-Myc activates cell growth by upregulating the expression of ribosomal RNAs and proteins and also by decreasing the expression of the genes encoding pro-apoptotic Bcl-2 proteins [30,32] .…”

Section: C-mycmentioning

confidence: 99%

The Canonical Wnt Signaling (Wnt/β-Catenin Pathway): A Potential Target for Cancer Prevention and Therapy

Najafi

2020

ibj

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Precise regulation of signal transduction pathways is crucial for normal animal development and for maintaining cellular and tissue homeostasis in adults. The Wnt/Frizzled-mediated signaling includes canonical and noncanonical signal transduction pathways. Upregulation or downregulation of the canonical Wnt signaling (or the Wnt/β-Catenin signal transduction) leads to a variety of human diseases, including cancers, neurodegenerative disorders, skin and bone diseases, and heart deficiencies. Therefore, Wnt/β-Catenin signal transduction is a potential clinical target for the treatment of not only human cancers but also some other human chronic diseases. Here, some recent results including those from my laboratory highlighting the role of Wnt/β-Catenin signal transduction in human cancers will be reviewed. After a brief overview on canonical Wnt signaling and introducing some critical β-Catenin/TCF-target genes, the interaction of canonical Wnt signaling with some common human cancers will be discussed. In the end, the different segments of the aforesaid signaling pathway, which have been considered as targets for clinical purposes, will be scrutinized.

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“…More than 70% of HGSOC tumors contain combined gains at PTK2 and MYC loci. Although MYC has oncogenic properties (Kumari et al, 2017), MYC copy number gains are not strongly correlated with increased MYC mRNA or protein levels in HGSOC patient tumors (Supplemental Figs. S2).…”

Section: Myc and Ptk2 Associations In Hgsocmentioning

confidence: 99%

“…Gains at 8q24 occur in the majority of HGSOC tumors and encompass the MYC oncogene at 8q24.21 (Gorringe, George et al, 2010). MYC facilitates pluripotent stem cell generation and contributes to HGSOC chemoresistance (Fagnocchi & Zippo, 2017, Kumari, Folk et al, 2017, Li, Bonazzoli et al, 2019. Although MYC expression is generally high in HGSOC, the clinical significance of this change remains unclear.…”

Section: Introductionmentioning

confidence: 99%

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

Osterman¹,

Ozmadenci²,

Kleinschmidt³

et al. 2019

Preprint

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= 175 words 7 Figures and 2 Tables AbstractGene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-b-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encoding KRAS, MYC and FAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neoadjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosis in vitro and in vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/b-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer. Running title (40 characters including spaces): FAK dependent signaling in ovarian cancerKeywords (5): b-catenin, FAK, Myc, ovarian cancer, platinum chemotherapy 3 Graphical Summary Key Points• High grade serous ovarian carcinoma tumors contain PTK2 (FAK) 8q24.3 gains associated with prognostic differences.• KMF, a new murine ovarian cancer model with K-Ras, Myc, and FAK gene gains and intrinsic platinum resistance.• FAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.• FAK facilitates a b-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.• FAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance. We thank our colleagues for helpful discussion and comments. We thank R. Winters (FCCC BRF manager) and D. Flieder (FCCC Pathology) for identifying, reviewing the cases, and for procuring patient tumor samples used in this study.

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The Dual Roles of MYC in Genomic Instability and Cancer Chemoresistance

Cited by 45 publications

References 154 publications

miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer

miR-27a is a master regulator of metabolic reprogramming and chemoresistance in colorectal cancer

The Canonical Wnt Signaling (Wnt/β-Catenin Pathway): A Potential Target for Cancer Prevention and Therapy

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

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