p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression

Amelio, Ivano; Mancini, Mara; Petrova, Varvara; Cairns, Rob A.; Vikhreva, P. N.; Nicolai, Sara; Marini, Alberto; Антонов, А.; Quesne, John Le; Acevedo, Juvenal Dario Baena; Dudek, Kate; Sozzi, Gabriella; Pastorino, Ugo; Knight, Richard; Mak, Tak W.; Melino, Gerry

doi:10.1073/pnas.1808314115

Cited by 115 publications

(104 citation statements)

References 40 publications

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“…BAF250A ( ARID1A ) and INI1 ( SMARCB1 ) genes seem to be predictive markers in ccRCC 32,33 due to that the lowest levels of these genes mRNAs were observed in A498 line. This finding suggests plausible influence of the Δ2‐6 HIF1A deletion notably BAF250a and INI1 subunits of SWI/SNF complex that interact with HIF‐1α, 28 and ARID1A positively correlate with HIF1A expression in ccRCC patients' samples. Moreover, the overexpression of both full‐length and truncated HIF‐1α∆2‐6 form leads to downregulation of some genes encoding subunits of SWI/SNF chromatin remodeling complex, for example, SMARCA2 /BRM, SMARCA4 /BRG1, and ARID1A /BAF250a.…”

Section: Discussionmentioning

confidence: 78%

“…HIF‐1α is involved in metabolism control, interacts with the SWI/SNF chromatin remodeling complex 28 and other bHLH‐PAS family proteins. Therefore, to evaluate differences in expression of selected genes in the most commonly used ccRCC cell lines we conducted the expression analysis of some genes encoding proteins belonging to bHLH‐PAS superfamily (EPAS1, ARNT), SWI/SNF subunits (ARID1A/BAF250a and SMARCB1/INI1) and genes encoding glycolysis enzymes (HK, ENO, LDHA, ALDO A, PKM2, and GAPDH) as well as lipid acid metabolism (CPT1A and PLIN2).…”

Section: Resultsmentioning

confidence: 99%

“…The high level of HIF1A transcript was detected using primers specific for exon 12, which is present in truncated HIF1A∆2‐6 form but not for primers specific to exon 3 and 6 found only in HIF1A full‐length CDS (Figure 5b). It is known that the intact form of HIF‐1α protein interacts with BRG1, a central ATPase subunit of the SWI/SNF chromatin remodeling complex in lung cancer 28 . The BRG1 level was assessed in HeLa cell line with transient overexpression of either full or truncated HIF‐1α forms.…”

Section: Resultsmentioning

confidence: 99%

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Various forms of HIF‐1α protein characterize the clear cell renal cell carcinoma cell lines

et al. 2020

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Renal cell carcinoma (RCC) represents around 2-3% of all malignancies diagnosed in adult patients. Most frequent (around 70-80% cases) and the most aggressive subtype is clear cell RCC (ccRCC). Mutations in VHL (von Hippel Lindau) gene, characteristic for this cancer type, lead to altered activity of the trimeric VBC (pVHL-elongin B-C) complex and consequently to HIF-1α stabilization. In this study, we present results of exhaustive investigation of HIF-1α alternative transcript variants abundance in A498, CAKI-1, and 786-O ccRCC cell lines. We proved the existence of truncated HIF-1α protein form (HIF1AΔ-6) in A498 and HIF1A gene rearrangements in 786-O cell lines. Subsequently, we found that HIF1AΔ2-6 was more stable than the full-length HIF-1α. Moreover, the shorter HIF-1α was insensitive for hypoxia and was overaccumulated after proteasome inhibitor treatment indicative of potential diversified roles of full-length and truncated HIF-1α forms in the cell. We also showed that A498, CAKI-1, and 786-O exhibit differential expression of various regulatory genes involved in the control of metabolic processes, that is, glucose and lipid metabolism, and encoding subunits of such machineries like SWI/SNF chromatin remodeling complex. Furthermore, these cell lines exhibited differential responses to axitinib, everolimus, and sunitinib-anticancer drugs-in normoxia and hypoxia as well as various alterations in metabolism-related Abbreviations: 2-OG, 2-oxoglutarate; ALDO, aldolase; ARD1, arrest-defective 1 acetyltransferase; ARNT, aryl hydrocarbon receptor nuclear translocator; bHLH, basic helix-loop-helix; ccRCC, clear cell renal cell carcinoma; CPT1A, carnitine palmitoyltransferase 1A; CUL2, cullin 2; DFO, deferoxamine; DMOG, dimethyloxaloglycine; ENO, enolase; EPAS1, endothelial PAS domain protein 1; EPO, erythropoietin; FBP1, fructose-1,6-bisphosphatase 1; FIH-1, factor inhibiting HIF-1; G6P, glucose-6-phosphatase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HIF1A, hypoxia inducible factor 1A; HK, hexokinase; HPH, HIF prolyl hydroxylase; HRE, hypoxia-responsive element; iNOS, inducible nitric oxide synthase; LDHA, lactate dehydrogenase A; PAS, Per-ARNT-Sim; PHD, prolyl hydroxylase; PLIN2, perilipin 2; PKM2, pyruvate kinase M2; RBX-1, Ring box 1; RCC, renal cell carcinoma; SMARCB1 (INI1), SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1; TCEB1, transcription elongation factor B (SIII); VHL, von Hippel-Lindau.

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Section: Discussionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Various forms of HIF‐1α protein characterize the clear cell renal cell carcinoma cell lines

et al. 2020

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“…Similarly, in a cancer mouse model obtained by hypoxic preconditioned non-small cell lung cancer xenotransplantation into immunocompromised mice, the depletion of mutant p53 was associated with reduced tumor growth that was reverted by the overexpression of laminin-γ2 or type VIIa1 collagen. Coherently, in human NSCLC patients, the expression of these ECM genes is correlated with HIF-1 activation exclusively in patients carrying p53 mutations, and is associated with a worse prognosis [116,117]. In response to hypoxia, p53 mutant forms a complex with hypoxia-inducible factor 1 (HIF-1) that physically binds the SWI/SNF chromatin remodeling complex, promoting expression of extracellular matrix (ECM) components such as Laminin-γ2 and type VIIa1 collagen (COL7A1).…”

Section: Role Of Mutant P53 Gain Of Function In Metabolism and Hypoxiamentioning

confidence: 97%

Do Mutations Turn p53 into an Oncogene?

Pitolli

Wang

Mancini

et al. 2019

IJMS

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The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.

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“…COLI fibers exhibited covalent crosslinking with prolyl 4-hydroxylase alpha 1 and prolyl 4-hydroxylase alpha 2 in differentiated cell types of triple-negative breast cancer, and the prolyl 4-hydroxylase alpha 1/HIF-1 axis increased chemoresistance [112,113]. Even mutant p53 regulated the expression of COL7A1 in NSCLC, not by influencing HIF-1 binding to DNA, but rather by inhibiting its transcriptional activity [114].…”

Section: The Reciprocity Between Collagen and Cancer Cells Under Hypomentioning

confidence: 99%

The role of collagen in cancer: from bench to bedside

et al. 2019

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Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.

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p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression

Cited by 115 publications

References 40 publications

Various forms of HIF‐1α protein characterize the clear cell renal cell carcinoma cell lines

Various forms of HIF‐1α protein characterize the clear cell renal cell carcinoma cell lines

Do Mutations Turn p53 into an Oncogene?

The role of collagen in cancer: from bench to bedside

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