Dissecting the Oncogenic Roles of Keratin 17 in the Hallmarks of Cancer

Baraks, Gabriella; Tseng, Robert; Pan, Chun‐Hao; Kasliwal, Saumya; Leiton, Cindy V.; Shroyer, Kenneth R.; Escobar‐Hoyos, Luisa F.

doi:10.1158/0008-5472.can-21-2522

Cited by 26 publications

(27 citation statements)

References 95 publications

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“…Keratin 17 has been underscored as an emerging diagnostic, prognostic, and predictive biomarker ( Yang, Zhang & Wang, 2019 ), based on preclinical and clinical cancer studies. According to Baraks et al (2022) , KRT17 is implicated in eight out of ten deadly hallmarks of cancer. KRT17 triggers the AKT-mediated signaling pathway and induces EMT, while it is strongly correlated with malignant transformation and worse prognosis in esophageal squamous cell carcinoma (ESCC) patients.…”

Section: Discussionmentioning

confidence: 99%

“In the light of evolution:” keratins as exceptional tumor biomarkers

Takan

Karakülah

Louka

et al. 2023

PeerJ

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Keratins (KRTs) are the intermediate filament-forming proteins of epithelial cells, classified, according to their physicochemical properties, into “soft” and “hard” keratins. They have a key role in several aspects of cancer pathophysiology, including cancer cell invasion and metastasis, and several members of the KRT family serve as diagnostic or prognostic markers. The human genome contains both, functional KRT genes and non-functional KRT pseudogenes, arranged in two uninterrupted clusters on chromosomes 12 and 17. This characteristic renders KRTs ideal for evolutionary studies. Herein, comprehensive phylogenetic analyses of KRT homologous proteins in the genomes of major taxonomic divisions were performed, so as to fill a gap in knowledge regarding the functional implications of keratins in cancer biology among tumor-bearing species. The differential expression profiles of KRTs in diverse types of cancers were investigated by analyzing high-throughput data, as well. Several KRT genes, including the phylogenetically conserved ones, were found to be deregulated across several cancer types and to participate in a common protein-protein interaction network. This indicates that, at least in cancer-bearing species, these genes might have been under similar evolutionary pressure, perhaps to support the same important function(s). In addition, semantic relations between KRTs and cancer were detected through extensive text mining. Therefore, by applying an integrative in silico pipeline, the evolutionary history of KRTs was reconstructed in the context of cancer, and the potential of using non-mammalian species as model organisms in functional studies on human cancer-associated KRT genes was uncovered.

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Section: Discussionmentioning

confidence: 99%

“In the light of evolution:” keratins as exceptional tumor biomarkers

Takan

Karakülah

Louka

et al. 2023

PeerJ

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“…One of the markers of cancer progression and other pathologies is the appearance or upregulation of several keratin genes, including K17, K19, K6/16, etc. Keratins are not only routinely used for cancer diagnostics, but are also applicable for the prediction of invasiveness and aggressiveness of the tumor cell [ 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 ]. Following the aberrant expression, the reorganization of the keratin cytoskeleton affects the cell motility, survival, and resistance to external factors, which results in tumor treatment responsiveness [ 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 ].…”

Section: Conclusion and Outlooksmentioning

confidence: 99%

A Kaleidoscope of Keratin Gene Expression and the Mosaic of Its Regulatory Mechanisms

Kalabusheva

Shtompel

Ulianov

et al. 2023

IJMS

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Keratins are a family of intermediate filament-forming proteins highly specific to epithelial cells. A combination of expressed keratin genes is a defining property of the epithelium belonging to a certain type, organ/tissue, cell differentiation potential, and at normal or pathological conditions. In a variety of processes such as differentiation and maturation, as well as during acute or chronic injury and malignant transformation, keratin expression undergoes switching: an initial keratin profile changes accordingly to changed cell functions and location within a tissue as well as other parameters of cellular phenotype and physiology. Tight control of keratin expression implies the presence of complex regulatory landscapes within the keratin gene loci. Here, we highlight patterns of keratin expression in different biological conditions and summarize disparate data on mechanisms controlling keratin expression at the level of genomic regulatory elements, transcription factors (TFs), and chromatin spatial structure.

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“…Alterations in tumor metabolism are intimately linked to tumor aggression and chemoresistance [29][30][31] . K17 expression has been reported to impact cancer cell metabolism 14 ; however, the detailed mechanisms remain unknown. To determine whether K17 promotes metabolic reprogramming, we analyzed primary PDAC tumor samples from The Cancer Genome Atlas (TCGA).…”

Section: K17 Drives Pyrimidine Biosynthesis That Is Associated With S...mentioning

confidence: 99%

“…K17 is normally expressed during embryogenesis, silenced in mature somatic tissues except in certain stem cell populations 10,11 , and re-expressed in cancer 12,13 . Beyond its role as a cytoskeletal protein, K17 has been reported to impact the hallmarks of cancer by regulating key oncogenic signaling pathways 14 . Among these hallmarks 15 , metabolic reprogramming is one that has not been comprehensively evaluated.…”

Section: Introductionmentioning

confidence: 99%

Targeting keratin 17-mediated reprogramming of de novo pyrimidine biosynthesis to overcome chemoresistance in pancreatic cancer

Pan

Chaika

Tseng

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death. We previously reported keratin 17 (K17) as a novel negative prognostic and predictive biomarker, whose overexpression confers the resistance to chemotherapies. Here, we investigated the mechanisms of chemoresistance and tumor-specific vulnerabilities that can be exploited for targeted therapies for K17-expressing PDAC. Unbiased metabolomic studies in isogenic PDAC models identified several key metabolic pathways that are upregulated in the presence of K17. We demonstrate that K17 increases pyrimidine biosynthesis, a pathway that has been linked to chemoresistance. Patient dataset analysis revealed that K17 expression and enzymes involved in pyrimidine, but not purine, de novo biosynthesis is associated with shorter patient survival. Rescue experiments showed that deoxycytidine (dC) and deoxythymidine (dT) were sufficient to promote resistance to Gemcitabine (a dC analog) and 5-fluorouracil (a dT analog), respectively. Furthermore, K17-expressing cells were more sensitive to Brequinar, a specific inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in de novo pyrimidine biosynthetic pathway. Targeting DHODH by small interfering RNA or by Brequinar with Gemcitabine synergistically inhibited the viability of K17-positive PDAC cells. Importantly, the combination of Gemcitabine and Brequinar significantly inhibited the growth of K17-expressing tumors and extended survival of mice bearing K17-expressing PDACs. Overall, we identified a novel pathway of chemoresistance and a metabolic target of which could lead to the development of a biomarker-based therapy for K17-expressing PDAC.

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Dissecting the Oncogenic Roles of Keratin 17 in the Hallmarks of Cancer

Cited by 26 publications

References 95 publications

“In the light of evolution:” keratins as exceptional tumor biomarkers

“In the light of evolution:” keratins as exceptional tumor biomarkers

A Kaleidoscope of Keratin Gene Expression and the Mosaic of Its Regulatory Mechanisms

Targeting keratin 17-mediated reprogramming of de novo pyrimidine biosynthesis to overcome chemoresistance in pancreatic cancer

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