<scp>FBXW</scp>7 regulates a mitochondrial transcription program by modulating <scp>MITF</scp>

Abbate, Franco; Badal, Brateil; Mendelson, Karen; Aydin, Iraz T.; Serasinghe, Madhavika N.; Iqbal, Ramiz; Mohammed, Jarvier N.; Solovyov, Alexander; Greenbaum, Benjamin; Chipuk, Jerry E.; Çelebi, Jülide Tok

doi:10.1111/pcmr.12704

Cited by 15 publications

(12 citation statements)

References 18 publications

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“…FBXW7 downregulation is, however, not always followed by a substantial increase in the levels of its target proteins as shown for MCL‐1 in melanoma cells . More recently, it has been evidenced that loss of FBXW7 cooperates with BRAF V600E in melanomagenesis, and enhances the mitochondrial metabolic program by modulating MITF protein levels in melanoma cells …”

Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Hartman

Sztiller-Sikorska

Czyż

2019

Molecular Carcinogenesis

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We have extensively studied the phenotypic heterogeneity of patient-derived melanoma cells. Here, whole-exome sequencing revealed novel variants of genes associated with the MAPK, NOTCH, Hippo, cell-cycle, senescence, and ubiquitindependent pathways, which could contribute to the observed phenotypic diversity between cell lines. Focusing on mutations in the MAPK pathway-associated genes, we found BRAF (BRAF V600E ) and RAS subtypes, including NRAS Q61R and the rare HRAS Q61R variant, and additional alterations potentially leading to different ERK1/2 activity. Both RAS Q61R cell lines harbored a MEK1 P124S variant and exerted a low level of phospho-MEK1/2. Activity of the MAPK pathway was further attenuated in NRAS Q61R /MEK P124S cells by trametinib, and this effect was also shown in HRAS Q61R / MEK P124S melanoma cells. The observed variability in doubling time might be a consequence of diverse MAPK and PI3K/AKT pathway activities, but not exclusively, as a senescence program was also executed to different extent in distinct melanoma cell lines. Low percentages of senescent cells might result from mutations in CDKN2A, E2F3, and EZH2, and a high c-MYC expression. Vemurafenib and trametinib induced senescence concomitantly with c-MYC downregulation and irrespectively of CDKN2A mutation, but the EZH2 S412C variant might limit senescence induction. Damaging alterations in Hippo pathway-associated genes were accompanied with variability in the phosphorylation level of YAP1/TAZ and CTGF expression. Our study also suggests opposite activity of NOTCH2 F1209V and NOTCH2 N2002S variants. Additionally, we found a novel FBXW7 V418M variant that retained its function in melanoma cells. The obtained molecular data might be further exploited in genotype-phenotype relationship studies and in identifying novel biomarkers and therapies for melanomas.

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Section: Discussionmentioning

confidence: 99%

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Hartman

Sztiller-Sikorska

Czyż

2019

Molecular Carcinogenesis

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“…Moreover, FBXW7 was also found to regulate the oncogene MITF in melanoma. In vitro silencing of FBXW7 in melanoma considerably enhanced MITF/PGC-1 signaling contributing to the augmentation of mitochondrial transcription program and may result in poor outcomes for the patients [163] (Table 1).…”

Section: Deregulation Of Fbxw7 In Different Types Of Cancermentioning

confidence: 99%

FBXW7 in Cancer: What Has Been Unraveled Thus Far?

Sailo

Banik

Girisa

et al. 2019

Cancers

132

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: The FBXW7 (F-box with 7 tandem WD40) protein encoded by the gene FBXW7 is one of the crucial components of ubiquitin ligase called Skp1-Cullin1-F-box (SCF) complex that aids in the degradation of many oncoproteins via the ubiquitin-proteasome system (UPS) thus regulating cellular growth. FBXW7 is considered as a potent tumor suppressor as most of its target substrates can function as potential growth promoters, including c-Myc, Notch, cyclin E, c-JUN, and KLF5. Its regulators include p53, C/EBP-δ, Numb, microRNAs, Pin 1, Hes-5, BMI1, Ebp2. Mounting evidence has indicated the involvement of aberrant expression of FBXW7 for tumorigenesis. Moreover, numerous studies have also shown its role in cancer cell chemosensitization, thereby demonstrating the importance of FBXW7 in the development of curative cancer therapy. This comprehensive review emphasizes on the targets, functions, regulators and expression of FBXW7 in different cancers and its involvement in sensitizing cancer cells to chemotherapeutic drugs.

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“…However, an increased reduction in the cell survival ratio was higher in the SNU-C5/WT cells than in the SNU-C5/5FUR cells (Figure 1A). Recent studies have suggested that PGC-1α enhances the mitochondrial energy metabolism and biogenesis in melanoma, colorectal cancer, and endometrial carcinoma [24,25,26]. Moreover, PGC-1α is related to the drug resistance that occurs in ovarian cancer cells [27].…”

Section: Resultsmentioning

confidence: 99%

PGC-1α Controls Mitochondrial Biogenesis in Drug-Resistant Colorectal Cancer Cells by Regulating Endoplasmic Reticulum Stress

Yun

Han

2019

IJMS

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Anti-cancer drug resistance is a serious issue for patients with colorectal cancer (CRC). Although recent studies have shown the mechanism by which CRC cells become drug resistant, novel strategies for overcoming this drug resistance have not yet been developed. To address this problem, we characterized 5-fluorouracil (5FU)-resistant CRC cells after treatment with 5FU, and focused on the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in these cells. In 5FU-resistant CRC cells, the 5FU did not considerably decrease the mitochondrial biogenesis or mitochondrial complex I and IV activities, and only partially decreased the antioxidant enzymatic activity, oxygen consumption ratio, and cell survival. The expression of PGC-1α was remarkably increased in the 5FU-resistant CRC cells compared with the 5FU-sensitive CRC cells. The 5FU-resistant CRC cells displayed enhanced mitochondrial biogenesis, oxidative phosphorylation, and antioxidant enzyme activities against 5FU-induced reactive oxygen species, because of the increased expression of PGC-1α. PGC-1α inhibited 5FU-induced endoplasmic reticulum (ER) stress in the 5FU-resistant CRC cells, resulting in the suppression of apoptosis. These findings reveal that PGC-1α plays an important role in drug resistance in 5FU-resistant CRC cells. Moreover, PGC-1α could serve as a novel target in patients with 5FU-resistant CRC.

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FBXW7 regulates a mitochondrial transcription program by modulating MITF

Cited by 15 publications

References 18 publications

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

FBXW7 in Cancer: What Has Been Unraveled Thus Far?

PGC-1α Controls Mitochondrial Biogenesis in Drug-Resistant Colorectal Cancer Cells by Regulating Endoplasmic Reticulum Stress

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