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22 pages, 5501 KiB

Open AccessArticle

Taspase1 Facilitates Topoisomerase IIβ-Mediated DNA Double-Strand Breaks Driving Estrogen-Induced Transcription

by Lisa Oelschläger, Paul Stahl, Farnusch Kaschani, Roland H. Stauber, Shirley K. Knauer and Astrid Hensel

Cells 2023, 12(3), 363; https://doi.org/10.3390/cells12030363 - 18 Jan 2023

Cited by 1 | Viewed by 1742

Abstract

The human protease Taspase1 plays a pivotal role in developmental processes and cancerous diseases by processing critical regulators, such as the leukemia proto-oncoprotein MLL. Despite almost two decades of intense research, Taspase1’s biology is, however, still poorly understood, and so far its cellular [...] Read more.

The human protease Taspase1 plays a pivotal role in developmental processes and cancerous diseases by processing critical regulators, such as the leukemia proto-oncoprotein MLL. Despite almost two decades of intense research, Taspase1’s biology is, however, still poorly understood, and so far its cellular function was not assigned to a superordinate biological pathway or a specific signaling cascade. Our data, gained by methods such as co-immunoprecipitation, LC-MS/MS and Topoisomerase II DNA cleavage assays, now functionally link Taspase1 and hormone-induced, Topoisomerase IIβ-mediated transient DNA double-strand breaks, leading to active transcription. The specific interaction with Topoisomerase IIα enhances the formation of DNA double-strand breaks that are a key prerequisite for stimulus-driven gene transcription. Moreover, Taspase1 alters the H3K4 epigenetic signature upon estrogen-stimulation by cleaving the chromatin-modifying enzyme MLL. As estrogen-driven transcription and MLL-derived epigenetic labelling are reduced upon Taspase1 siRNA-mediated knockdown, we finally characterize Taspase1 as a multifunctional co-activator of estrogen-stimulated transcription. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Regulation of Cancer)

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17 pages, 4209 KiB

Open AccessArticle

MST4: A Potential Oncogene and Therapeutic Target in Breast Cancer

by Ritu Arora, Jin-Hwan Kim, Ayechew A. Getu, Anusha Angajala, Yih-Lin Chen, Bin Wang, Andrea G. Kahn, Hong Chen, Latif Reshi, Jianrong Lu, Wenling Zhang, Ming Zhou and Ming Tan

Cells 2022, 11(24), 4057; https://doi.org/10.3390/cells11244057 - 15 Dec 2022

Cited by 5 | Viewed by 2414

Abstract

The mammalian STE 20-like protein kinase 4 (MST4) gene is highly expressed in several cancer types, but little is known about the role of MST4 in breast cancer, and the function of MST4 during epithelial-mesenchymal transition (EMT) has not been fully elucidated. Here [...] Read more.

The mammalian STE 20-like protein kinase 4 (MST4) gene is highly expressed in several cancer types, but little is known about the role of MST4 in breast cancer, and the function of MST4 during epithelial-mesenchymal transition (EMT) has not been fully elucidated. Here we report that overexpression of MST4 in breast cancer results in enhanced cell growth, migration, and invasion, whereas inhibition of MST4 expression significantly attenuates these properties. Further study shows that MST4 promotes EMT by activating Akt and its downstream signaling molecules such as E-cadherin/N-cadherin, Snail, and Slug. MST4 also activates AKT and its downstream pro-survival pathway. Furthermore, by analyzing breast cancer patient tissue microarray and silicon datasets, we found that MST4 expression is much higher in breast tumor tissue compared to normal tissue, and significantly correlates with cancer stage, lymph node metastasis and a poor overall survival rate (p < 0.05). Taken together, our findings demonstrate the oncogenic potential of MST4 in breast cancer, highlighting its role in cancer cell proliferation, migration/invasion, survival, and EMT, suggesting a possibility that MST4 may serve as a novel therapeutic target for breast cancer. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Regulation of Cancer)

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20 pages, 10361 KiB

Open AccessArticle

Epithelial–Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress

by Mingwei Liang, Jennifer W. Li, Huacheng Luo, Sarah Lulu, Ozlem Calbay, Anitha Shenoy, Ming Tan, Brian K. Law, Shuang Huang, Tsan Sam Xiao, Hao Chen, Lizi Wu, Jia Chang and Jianrong Lu

Cells 2022, 11(14), 2208; https://doi.org/10.3390/cells11142208 - 15 Jul 2022

Cited by 2 | Viewed by 2344

Abstract

Epithelial–mesenchymal transition (EMT) is implicated in tumor metastasis and therapeutic resistance. It remains a challenge to target cancer cells that have undergone EMT. The Snail family of key EMT-inducing transcription factors directly binds to and transcriptionally represses not only epithelial genes but also [...] Read more.

Epithelial–mesenchymal transition (EMT) is implicated in tumor metastasis and therapeutic resistance. It remains a challenge to target cancer cells that have undergone EMT. The Snail family of key EMT-inducing transcription factors directly binds to and transcriptionally represses not only epithelial genes but also a myriad of additional genomic targets that may carry out significant biological functions. Therefore, we reasoned that EMT inherently causes various concomitant phenotypes, some of which may create targetable vulnerabilities for cancer treatment. In the present study, we found that Snail transcription factors bind to the promoters of multiple genes encoding subunits of the AMP-activated protein kinase (AMPK) complex, and expression of AMPK genes was markedly downregulated by EMT. Accordingly, high AMPK expression in tumors correlated with epithelial cell markers and low AMPK expression in tumors was strongly associated with adverse prognosis. AMPK is the principal sensor of cellular energy status. In response to energy stress, AMPK is activated and critically reprograms cellular metabolism to restore energy homeostasis and maintain cell survival. We showed that activation of AMPK by energy stress was severely impaired by EMT. Consequently, EMT cancer cells became hypersensitive to a variety of energy stress conditions and primarily underwent pyroptosis, a regulated form of necrotic cell death. Collectively, the study suggests that EMT impedes the activation of AMPK signaling induced by energy stress and sensitizes cancer cells to pyroptotic cell death under energy stress conditions. Therefore, while EMT promotes malignant progression, it concurrently induces collateral vulnerabilities that may be therapeutically exploited. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Regulation of Cancer)

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17 pages, 10493 KiB

Open AccessArticle

Characterization of Collapsin Response Mediator Protein 2 in Colorectal Cancer Progression in Subjects with Diabetic Comorbidity

by Yih-Hsin Chang, Hui-Ju Yang, Huan-Wen Chen, Chiao-Wan Hsiao, Yi-Chen Hsieh, Yu-Wei Chan, Shu-Wen Chang, Wei-Lun Hwang, Wei-Shone Chen, Hou-Hsuan Cheng, Teh-Ying Chou, Fu-Pang Chang, Hsiang-Ling Ho, Fang-Yeh Chu, Yu-Li Lo, Chun-Jung Chen, Hui-Fang Tsai and Ming-Yuh Shiau

Cells 2022, 11(4), 727; https://doi.org/10.3390/cells11040727 - 18 Feb 2022

Cited by 2 | Viewed by 1951

Abstract

Background: Common demographic risk factors are identified in colorectal cancer (CRC) and type 2 diabetes mellitus (DM), nevertheless, the molecular link and mechanism for CRC-DM comorbidity remain elusive. Dysregulated glycogen synthase kinase-3 beta under metabolic imbalance is suggested to accelerate CRC pathogenesis/progression via [...] Read more.

Background: Common demographic risk factors are identified in colorectal cancer (CRC) and type 2 diabetes mellitus (DM), nevertheless, the molecular link and mechanism for CRC-DM comorbidity remain elusive. Dysregulated glycogen synthase kinase-3 beta under metabolic imbalance is suggested to accelerate CRC pathogenesis/progression via regulating collpasin response mediator protein-2 (CRMP2). Accordingly, roles of CRMP2 in CRC and CRC-DM patients were investigated for elucidating the molecular convergence of CRC and DM. Methods: CRMP2 profile in tumor tissues from CRC and CRC-DM patients was investigated to explore the link between CRC and DM etiology. Meanwhile, molecular mechanism of glucose to regulate CRMP2 profile and CRC characteristics was examined in vitro and in vivo. Results: CRMP2 was significantly lower in tumor lesions and associated with advanced tumor stage in CRC-DM patients. Physiological hyperglycemia suppressed CRMP2 expression/activity and augmented malignant characteristics of CRC cells. Hyperglycemia promotes actin de-polymerization, cytoskeleton flexibility and cell proliferation/metastasis by downregulating CRMP2 profile and thus contributes to CRC disease progression. Conclusions: This study uncovers molecular evidence to substantiate and elucidate the link between CRC and T2DM, as well as characterizing the roles of CRMP2 in CRC-DM. Accordingly, altered metabolic adaptations are promising targets for anti-diabetic and cancer strategies. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Regulation of Cancer)

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15 pages, 3769 KiB

Open AccessArticle

Discovery of a Novel Aminocyclopropenone Compound That Inhibits BRD4-Driven Nucleoporin NUP210 Expression and Attenuates Colorectal Cancer Growth

by Hiroya Kondo, Kenji Mishiro, Yuki Iwashima, Yujia Qiu, Akiko Kobayashi, Keesiang Lim, Takahiro Domoto, Toshinari Minamoto, Kazuma Ogawa, Munetaka Kunishima, Masaharu Hazawa and Richard W. Wong

Cells 2022, 11(3), 317; https://doi.org/10.3390/cells11030317 - 18 Jan 2022

Cited by 3 | Viewed by 3169

Abstract

Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic “readers” of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component [...] Read more.

Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic “readers” of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component of the nuclear pore complex (NPC), is a determinant of cancer malignancy, but BRD4-driven changes of NPC composition remain poorly understood. Here, we developed novel aminocyclopropenones and investigated their biological effects on cancer cell growth and BRD4 functions. Among 21 compounds developed here, we identified aminocyclopropenone 1n (ACP-1n) with the strongest inhibitory effects on the growth of the cancer cell line HCT116. ACP-1n blocked BRD4 functions by preventing its phase separation ability both in vitro and in vivo, attenuating the expression levels of BRD4-driven MYC. Notably, ACP-1n significantly reduced the nuclear size with concomitant suppression of the level of the NPC protein nucleoporin NUP210. Furthermore, NUP210 is in a BRD4-dependent manner and silencing of NUP210 was sufficient to decrease nucleus size and cellular growth. In conclusion, our findings highlighted an aminocyclopropenone compound as a novel therapeutic drug blocking BRD4 assembly, thereby preventing BRD4-driven oncogenic functions in cancer cells. This study facilitates the development of the next generation of effective and potent inhibitors of epigenetic bromodomains and extra-terminal (BET) protein family. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Regulation of Cancer)

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Review

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15 pages, 1432 KiB

Open AccessReview

Targeting ARID1A-Deficient Cancers: An Immune-Metabolic Perspective

by Timofey Lebedev, Rubina Kousar, Bbumba Patrick, Muhammad Usama, Meng-Kuei Lee, Ming Tan and Xing-Guo Li

Cells 2023, 12(6), 952; https://doi.org/10.3390/cells12060952 - 21 Mar 2023

Cited by 2 | Viewed by 2680

Abstract

Epigenetic remodeling and metabolic reprogramming, two well-known cancer hallmarks, are highly intertwined. In addition to their abilities to confer cancer cell growth advantage, these alterations play a critical role in dynamically shaping the tumor microenvironment and antitumor immunity. Recent studies point toward the [...] Read more.

Epigenetic remodeling and metabolic reprogramming, two well-known cancer hallmarks, are highly intertwined. In addition to their abilities to confer cancer cell growth advantage, these alterations play a critical role in dynamically shaping the tumor microenvironment and antitumor immunity. Recent studies point toward the interplay between epigenetic regulation and metabolic rewiring as a potentially targetable Achilles’ heel in cancer. In this review, we explore the key metabolic mechanisms that underpin the immunomodulatory role of AT-rich interaction domain 1A (ARID1A), the most frequently mutated epigenetic regulator across human cancers. We will summarize the recent advances in targeting ARID1A-deficient cancers by harnessing immune-metabolic vulnerability elicited by ARID1A deficiency to stimulate antitumor immune response, and ultimately, to improve patient outcome. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Regulation of Cancer)

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15 pages, 969 KiB

Open AccessReview

The Emerging Roles and Clinical Potential of circSMARCA5 in Cancer

by Changning Xue, Jianxia Wei, Mengna Li, Shipeng Chen, Lemei Zheng, Yuting Zhan, Yumei Duan, Hongyu Deng, Wei Xiong, Guiyuan Li, Hui Li and Ming Zhou

Cells 2022, 11(19), 3074; https://doi.org/10.3390/cells11193074 - 30 Sep 2022

Cited by 4 | Viewed by 1990

Abstract

Circular RNAs (circRNAs) are a type of endogenous non-coding RNA and a critical epigenetic regulation way that have a closed-loop structure and are highly stable, conserved, and tissue-specific, and they play an important role in the development of many diseases, including tumors, neurological [...] Read more.

Circular RNAs (circRNAs) are a type of endogenous non-coding RNA and a critical epigenetic regulation way that have a closed-loop structure and are highly stable, conserved, and tissue-specific, and they play an important role in the development of many diseases, including tumors, neurological diseases, and cardiovascular diseases. CircSMARCA5 is a circRNA formed by its parental gene SMARCA5 via back splicing which is dysregulated in expression in a variety of tumors and is involved in tumor development with dual functions as an oncogene or tumor suppressor. It not only serves as a competing endogenous RNA (ceRNA) by binding to various miRNAs, but it also interacts with RNA binding protein (RBP), regulating downstream gene expression; it also aids in DNA damage repair by regulating the transcription and expression of its parental gene. This review systematically summarized the expression and characteristics, dual biological functions, and molecular regulatory mechanisms of circSMARCA5 involved in carcinogenesis and tumor progression as well as the potential applications in early diagnosis and gene targeting therapy in tumors. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Regulation of Cancer)

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23 pages, 1238 KiB

Open AccessReview

Targeting Epigenetic Modifiers of Tumor Plasticity and Cancer Stem Cell Behavior

by Vigneshwari Easwar Kumar, Roshni Nambiar, Cristabelle De Souza, Audrey Nguyen, Jeremy Chien and Kit S. Lam

Cells 2022, 11(9), 1403; https://doi.org/10.3390/cells11091403 - 21 Apr 2022

Cited by 15 | Viewed by 3072

Abstract

Tumor heterogeneity poses one of the greatest challenges to a successful treatment of cancer. Tumor cell populations consist of different subpopulations that have distinct phenotypic and genotypic profiles. Such variability poses a challenge in successfully targeting all tumor subpopulations at the same time. [...] Read more.

Tumor heterogeneity poses one of the greatest challenges to a successful treatment of cancer. Tumor cell populations consist of different subpopulations that have distinct phenotypic and genotypic profiles. Such variability poses a challenge in successfully targeting all tumor subpopulations at the same time. Relapse after treatment has been previously explained using the cancer stem cell model and the clonal evolution model. Cancer stem cells are an important subpopulation of tumor cells that regulate tumor plasticity and determine therapeutic resistance. Tumor plasticity is controlled by genetic and epigenetic changes of crucial genes involved in cancer cell survival, growth and metastasis. Targeting epigenetic modulators associated with cancer stem cell survival can unlock a promising therapeutic approach in completely eradicating cancer. Here, we review various factors governing epigenetic dysregulation of cancer stem cells ranging from the role of epigenetic mediators such as histone and DNA methyltransferases, histone deacetylases, histone methyltransferases to various signaling pathways associated with cancer stem cell regulation. We also discuss current treatment regimens targeting these factors and other promising inhibitors in clinical trials. Full article

(This article belongs to the Special Issue Epigenetic and Metabolic Regulation of Cancer)

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