A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models

Zhong, Zheng; Harmston, Nathan; Wood, Kris C.; Madan, Babita; Virshup, David M.

doi:10.1172/jci156305

Cited by 16 publications

(36 citation statements)

References 85 publications

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“…In pancreatic cancer, loss of P300 could mediate Wnt/β-catenin independent tumor growth, thus leading to resistance to PORCN inhibition. 130 P300 inhibition also rendered bladder cancer cells resistant to doxorubicin. 131 On the contrary, P300 encoding gene EP300 was able to combine with the COL1A2 promoter to activate its expression, thus promoting apatinib resistance in GC cells.…”

Section: Histone Modifications and Drug Resistancementioning

confidence: 99%

Targeting epigenetic regulators to overcome drug resistance in cancers

Wang

2023

Sig Transduct Target Ther

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Drug resistance is mainly responsible for cancer recurrence and poor prognosis. Epigenetic regulation is a heritable change in gene expressions independent of nucleotide sequence changes. As the common epigenetic regulation mechanisms, DNA methylation, histone modification, and non-coding RNA regulation have been well studied. Increasing evidence has shown that aberrant epigenetic regulations contribute to tumor resistance. Therefore, targeting epigenetic regulators represents an effective strategy to reverse drug resistance. In this review, we mainly summarize the roles of epigenetic regulation in tumor resistance. In addition, as the essential factors for epigenetic modifications, histone demethylases mediate the histone or genomic DNA modifications. Herein, we comprehensively describe the functions of the histone demethylase family including the lysine-specific demethylase family, the Jumonji C-domain-containing demethylase family, and the histone arginine demethylase family, and fully discuss their regulatory mechanisms related to cancer drug resistance. In addition, therapeutic strategies, including small-molecule inhibitors and small interfering RNA targeting histone demethylases to overcome drug resistance, are also described.

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Section: Histone Modifications and Drug Resistancementioning

confidence: 99%

Targeting epigenetic regulators to overcome drug resistance in cancers

Wang

2023

Sig Transduct Target Ther

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“…In glioma, P300 mediates glioma stem cell adaptive response to therapeutic stress [ 74 ]. On the other hand, in pancreatic cancer, the p300/GATA6 axis determines differentiation and Wnt dependency, and loss of EP300 leads to a phenotypic transition from the classical subtype to the de-differentiated basal-like/squamous subtype of pancreatic cancer due to the attenuation of the GATA6-regulated differentiation program [ 75 ]. Similarly, Asaduzzaman et al [ 76 ] have demonstrated that the modulation of EP300 expression alters cancer stem cell markers and anchorage independence in basal-like breast cancer models.…”

Section: Several Brd Family Members Play a Fundamental Role In Cancer...mentioning

confidence: 99%

Bromodomain (BrD) Family Members as Regulators of Cancer Stemness—A Comprehensive Review

Czerwińska

Maćkiewicz²

2023

IJMS

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Epigenetic mechanisms involving DNA methylation and chromatin modifications have emerged as critical facilitators of cancer heterogeneity, substantially affecting cancer development and progression, modulating cell phenotypes, and enhancing or inhibiting cancer cell malignant properties. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins are essential to maintaining the cancer stem cell (CSC)-like state. With increased tumor-initiating capacities and self-renewal potential, CSCs promote tumor growth, provide therapy resistance, spread tumors, and facilitate tumor relapse after treatment. In this review, we characterized the epigenetic mechanisms that regulate the acquisition and maintenance of cancer stemness concerning selected epigenetic factors belonging to the Bromodomain (BrD) family of proteins. An increasing number of BrD proteins reinforce cancer stemness, supporting the maintenance of the cancer stem cell population in vitro and in vivo via the utilization of distinct mechanisms. As bromodomain possesses high druggable potential, specific BrD proteins might become novel therapeutic targets in cancers exhibiting de-differentiated tumor characteristics.

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“…Our previous in vivo CRISPR screen identified several genes whose knockout caused resistance to a PORCN inhibitor 18 . Most of these genes are known negative regulators of Wnt pathway, e.g., APC and AXIN1, so that their knockout provides downstream activation of Wnt/β-catenin signaling.…”

Section: Recurrent Fbxw7 Mutations In Rnf43-mutant/rspo-fusion Cancersmentioning

confidence: 99%

“…Wnt inhibition leads to cell cycle arrest and differentiation rather than cell death in Wntaddicted cancers 14,18,26,28 . We examined if the molecular response to anti-Wnt therapies differed in the FBXW7-wildtype versus mutant tumors (Fig.…”

Section: Fbxw7 Mutation Status Predicts Resistance To Wnt Inhibitionmentioning

confidence: 99%

“…To identify potential drug resistance mechanisms, we previously performed an in vivo CRISPR gene knockout screen during PORCN inhibitor treatment in mice bearing RNF43mutant pancreatic cancer xenografts. This screen identified gene candidates whose loss could cause Wnt independence and led to the discovery that defects in the p300/GATA6/differentiation axis can bypass the anti-differentiation role of Wnt signaling specifically in pancreatic cancer 18 . However, this does not appear to explain the drug resistance observed in those non-pancreatic cancer models, most notably in colorectal cancers.…”

Section: Introductionmentioning

confidence: 99%

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RecurrentFBXW7mutations bypass Wnt/β-catenin addiction in cancer

Zhong,

Virshup

2023

Preprint

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Pathologic Wnt/β-catenin signaling drives various cancers, leading to multiple approaches to drug this pathway. Appropriate patient selection can maximize success of these interventions. Wnt ligand addiction is a druggable vulnerability in RNF43-mutant/RSPO-fusion cancers. However, pharmacologically targeting the biogenesis of Wnt ligands, e.g., with PORCN inhibitors, has shown mixed therapeutic responses, possibly due to tumor heterogeneity. Here we show that the tumor suppressor FBXW7 is frequently mutated in RNF43-mutant/RSPO-fusion tumors, and FBXW7 mutations cause intrinsic resistance to anti-Wnt therapies. Mechanistically, inactivation of FBXW7 stabilizes multiple oncoproteins including Cyclin E and MYC, and antagonizes the cytostatic effect of Wnt inhibitors. Moreover, although FBXW7 mutations do not mitigate β-catenin degradation upon Wnt inhibition, FBXW7-mutant RNF43-mutant/RSPO-fusion cancers instead lose dependence on β-catenin signaling, accompanied by dedifferentiation and loss of lineage specificity. These FBXW7-mutant Wnt/β-catenin-independent tumors are susceptible to multi-CDK inhibition by dinaciclib. An in-depth understanding of primary resistance to anti-Wnt/β-catenin therapies allows for more appropriate patient selection and use of alternative mechanism-based therapies.

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A p300/GATA6 axis determines differentiation and Wnt dependency in pancreatic cancer models

Cited by 16 publications

References 85 publications

Targeting epigenetic regulators to overcome drug resistance in cancers

Targeting epigenetic regulators to overcome drug resistance in cancers

Bromodomain (BrD) Family Members as Regulators of Cancer Stemness—A Comprehensive Review

RecurrentFBXW7mutations bypass Wnt/β-catenin addiction in cancer

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