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Article ; Online: STK11 loss leads to YAP1-mediated transcriptional activation in human KRAS-driven lung adenocarcinoma cell lines.

Lenahan, Sean M / Sarausky, Hailey M / Deming, Paula / Seward, David J

2023 Volume 31, Issue 1, Page(s) 1–8

Abstract: Serine Threonine Kinase 11 (STK11) loss of function (LoF) correlates with anti-PD-1 therapy resistance in patients with KRAS-driven lung adenocarcinoma (LUAD). The molecular mechanisms governing this observation remain unclear and represent a critical ... ...

Abstract	Serine Threonine Kinase 11 (STK11) loss of function (LoF) correlates with anti-PD-1 therapy resistance in patients with KRAS-driven lung adenocarcinoma (LUAD). The molecular mechanisms governing this observation remain unclear and represent a critical outstanding question in the field of lung oncology. As an initial approach to understand this phenomenon, we knocked-out (KO) STK11 in multiple KRAS-driven, STK11-competent human LUAD cell lines and performed whole transcriptome analyses to identify STK11-loss-dependent differential gene expression. Subsequent pathway enrichment studies highlighted activation of the HIPPO/YAP1 signaling axis, along with the induction of numerous tumor-intrinsic cytokines. To validate that YAP1-mediated transcriptional activation occurs in response to STK11 loss, we pursued YAP1 perturbation as a strategy to restore an STK11-competent gene expression profile in STK11-KO LUAD cell lines. Together, our data link STK11 loss with YAP1-mediated transcriptional activation, including the upregulation of immune-evasion promoting cytokines IL-6, CXCL8 and CXCL2. Further, our results raise the intriguing possibility that YAP1 antagonism may represent a therapeutic approach to counter anti-PD-1 therapy resistance in STK11-null, KRAS-driven LUADs by modulating tumor-intrinsic gene expression to promote a "hot" tumor immune microenvironment.
MeSH term(s)	Humans ; Lung Neoplasms/pathology ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Transcriptional Activation ; AMP-Activated Protein Kinase Kinases ; Mutation ; Adenocarcinoma of Lung/genetics ; Adenocarcinoma of Lung/drug therapy ; Cell Line, Tumor ; Cytokines/metabolism ; Tumor Microenvironment
Chemical Substances	Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; AMP-Activated Protein Kinase Kinases (EC 2.7.11.3) ; Cytokines ; KRAS protein, human ; STK11 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2023-11-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1212513-1
ISSN	1476-5500 ; 0929-1903
ISSN (online)	1476-5500
ISSN	0929-1903
DOI	10.1038/s41417-023-00687-y
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Article ; Online: Oncologic Outcomes for Squamous Cell Carcinoma In Situ With a Clinically Resolved Biopsy Site Managed by Watchful Waiting.

Logan, Sam / Porter, Hannah J / Lowry, Joy / Carpenter, Cari / Seward, David J / Holmes, Todd / Goldman, Glenn / Bui, Melanie R

Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.

2024

Abstract: Background: Treatment option decisions for low-risk squamous cell carcinoma in situ (SCCIS) are hampered by a paucity of management-type-specific outcomes data.: Objective: Describe SCCIS tumor outcomes managed by watchful waiting and risk factors ... ...

Abstract	Background: Treatment option decisions for low-risk squamous cell carcinoma in situ (SCCIS) are hampered by a paucity of management-type-specific outcomes data. Objective: Describe SCCIS tumor outcomes managed by watchful waiting and risk factors associated with poor cancer outcomes. Materials and methods: Retrospective cohort study. Setting: Single academic hospital in a rural setting. Patients: Adults with SCCIS diagnosed between January 01, 2014, and December 31, 2016. Main Outcomes and Measures: Hazard ratios (HRs) for local recurrence (LR), nodal metastases (NM), distant metastases (DM), and disease-specific death (DSD). Results: A total of 411 consecutive SCCIS tumors that were considered clinically resolved at follow-up and managed with watchful waiting were included. Seventeen tumors recurred locally. No instances of NM, DM, or DSD were identified. Multivariate analysis found that solid-organ transplant recipient status conferred the highest risk of local recurrence [HR, 9.979 (95% CI, 2.249-39.69)]. Additional risk factors predicting LR include anatomic location on the vermilion lip or ear [HR, 9.744 (95% CI, 1.420-69.28)], anatomic location on the head and neck [HR, 6.687 (95% CI, 1.583-36.15)], and a biopsy with tumor extending to the deep edge [HR, 6.562 (95% CI, 1.367-39.04)]. Conclusion: Watchful waiting for SCCIS with a clinically resolved biopsy site has a local recurrence rate of 4%.
Language	English
Publishing date	2024-05-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1227586-4
ISSN	1524-4725 ; 1076-0512
ISSN (online)	1524-4725
ISSN	1076-0512
DOI	10.1097/DSS.0000000000004202
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Article ; Online: Glutaredoxin attenuates glutathione levels via deglutathionylation of Otub1 and subsequent destabilization of system x

Aboushousha, Reem / van der Velden, Jos / Hamilton, Nicholas / Peng, Zhihua / MacPherson, Maximilian / Erickson, Cuixia / White, Sheryl / Wouters, Emiel F M / Reynaert, Niki L / Seward, David J / Li, Jianing / Janssen-Heininger, Yvonne M W

Science advances

2023 Volume 9, Issue 37, Page(s) eadi5192

Abstract: Glutathione (GSH) is a critical component of the cellular redox system that combats oxidative stress. The glutamate-cystine antiporter, system ... ...

Abstract	Glutathione (GSH) is a critical component of the cellular redox system that combats oxidative stress. The glutamate-cystine antiporter, system x
MeSH term(s)	Glutaredoxins ; Cystine ; Biological Transport ; Glutamic Acid ; Glutathione
Chemical Substances	Glutaredoxins ; Cystine (48TCX9A1VT) ; Glutamic Acid (3KX376GY7L) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2023-09-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adi5192
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Article ; Online: Corrigendum to "Spatiotemporal higher-order chromatin landscape of human histone gene clusters at histone locus bodies during the cell cycle in breast cancer progression" [Gene 872 (2023) 147441].

Ghule, Prachi N / Boyd, Joseph R / Kabala, Fleur / Fritz, Andrew J / Bouffard, Nicole A / Gao, Cong / Bright, Kathleen / Macfarlane, Jill / Seward, David J / Pegoraro, Gianluca / Misteli, Tom / Lian, Jane B / Frietze, Seth / Stein, Janet L / van Wijnen, Andre J / Stein, Gary S

Gene

2023 Volume 873, Page(s) 147469

Language	English
Publishing date	2023-05-11
Publishing country	Netherlands
Document type	Published Erratum
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2023.147469
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Article ; Online: Spatiotemporal higher-order chromatin landscape of human histone gene clusters at histone locus bodies during the cell cycle in breast cancer progression.

Gene

2023 Volume 872, Page(s) 147441

Abstract: Human Histone Locus Bodies (HLBs) are nuclear subdomains comprised of clustered histone genes that are coordinately regulated throughout the cell cycle. We addressed temporal-spatial higher-order genome organization for time-dependent chromatin ... ...

Abstract	Human Histone Locus Bodies (HLBs) are nuclear subdomains comprised of clustered histone genes that are coordinately regulated throughout the cell cycle. We addressed temporal-spatial higher-order genome organization for time-dependent chromatin remodeling at HLBs that supports control of cell proliferation. Proximity distances of specific genomic contacts within histone gene clusters exhibit subtle changes during the G1 phase in MCF10 breast cancer progression model cell lines. This approach directly demonstrates that the two principal histone gene regulatory proteins, HINFP (H4 gene regulator) and NPAT, localize at chromatin loop anchor-points, denoted by CTCF binding, supporting the stringent requirement for histone biosynthesis to package newly replicated DNA as chromatin. We identified a novel enhancer region located ∼ 2 MB distal to histone gene sub-clusters on chromosome 6 that consistently makes genomic contacts with HLB chromatin and is bound by NPAT. During G1 progression the first DNA loops form between one of three histone gene sub-clusters bound by HINFP and the distal enhancer region. Our findings are consistent with a model that the HINFP/NPAT complex controls the formation and dynamic remodeling of higher-order genomic organization of histone gene clusters at HLBs in early to late G1 phase to support transcription of histone mRNAs in S phase.
MeSH term(s)	Humans ; Female ; Histones/genetics ; Histones/metabolism ; Chromatin/genetics ; Breast Neoplasms/genetics ; Cell Cycle/genetics ; Cell Cycle Proteins/genetics ; Nuclear Bodies ; Multigene Family
Chemical Substances	Histones ; Chromatin ; Cell Cycle Proteins
Language	English
Publishing date	2023-04-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2023.147441
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Article ; Online: Diagnosing calciphylaxis: A series of cases with both imaging and tissue biopsy.

Alniemi, Dema T / Kanner, Christopher / Stowman, Anne M / Knapp, Maxwell / McGevna, Laura / Seward, David J / Bui, Melanie R

Journal of the American Academy of Dermatology

2020 Volume 88, Issue 5, Page(s) 1117–1119

MeSH term(s)	Humans ; Calciphylaxis/diagnosis ; Calciphylaxis/pathology ; Diagnostic Imaging ; Kidney Failure, Chronic/complications ; Kidney Failure, Chronic/therapy ; Biopsy
Language	English
Publishing date	2020-06-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	603641-7
ISSN	1097-6787 ; 0190-9622
ISSN (online)	1097-6787
ISSN	0190-9622
DOI	10.1016/j.jaad.2020.05.111
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Article ; Online: Cutaneous squamous cell carcinoma of the forearm: Clinical features and outcomes at a single academic tertiary care center in a rural setting.

Johnston, Margaret / Carpenter, Cari E / Potter, Kathryn / Knapp, Maxwell / Shea, Katelyn / Seward, David J / Dayman, Caitlyn / Bui, Melanie R

Journal of the American Academy of Dermatology

2020 Volume 85, Issue 3, Page(s) 778–780

MeSH term(s)	Carcinoma, Squamous Cell/epidemiology ; Carcinoma, Squamous Cell/therapy ; Forearm ; Head and Neck Neoplasms ; Humans ; Retrospective Studies ; Skin Neoplasms/epidemiology ; Tertiary Care Centers
Language	English
Publishing date	2020-08-27
Publishing country	United States
Document type	Letter
ZDB-ID	603641-7
ISSN	1097-6787 ; 0190-9622
ISSN (online)	1097-6787
ISSN	0190-9622
DOI	10.1016/j.jaad.2020.08.089
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Article ; Online: Spatiotemporal higher-order chromatin landscape of human histone gene clusters at histone locus bodies during the cell cycle in breast cancer progression

Ghule, Prachi N. / Boyd, Joseph R. / Kabala, Fleur / Fritz, Andrew J. / Bouffard, Nicole A. / Gao, Cong / Bright, Kathleen / Macfarlane, Jill / Seward, David J. / Pegoraro, Gianluca / Misteli, Tom / Lian, Jane B. / Frietze, Seth / Stein, Janet L. / Van Wijnen, Andre J. / Stein, Gary S.

Gene. 2023 July, v. 872 p.147441-

2023

Abstract	Human Histone Locus Bodies (HLBs) are nuclear subdomains comprised of clustered histone genes that are coordinately regulated throughout the cell cycle. We addressed temporal-spatial higher-order genome organization for time-dependent chromatin remodeling at HLBs that supports control of cell proliferation. Proximity distances of specific genomic contacts within histone gene clusters exhibit subtle changes during the G1 phase in MCF10 breast cancer progression model cell lines. This approach directly demonstrates that the two principal histone gene regulatory proteins, HINFP (H4 gene regulator) and NPAT, localize at chromatin loop anchor-points, denoted by CTCF binding, supporting the stringent requirement for histone biosynthesis to package newly replicated DNA as chromatin. We identified a novel enhancer region located ∼ 2 MB distal to histone gene sub-clusters on chromosome 6 that consistently makes genomic contacts with HLB chromatin and is bound by NPAT. During G1 progression the first DNA loops form between one of three histone gene sub-clusters bound by HINFP and the distal enhancer region. Our findings are consistent with a model that the HINFP/NPAT complex controls the formation and dynamic remodeling of higher-order genomic organization of histone gene clusters at HLBs in early to late G1 phase to support transcription of histone mRNAs in S phase.
Keywords	DNA ; biosynthesis ; breast neoplasms ; cell proliferation ; chromatin ; genomics ; histones ; humans ; interphase ; loci ; models ; neoplasm progression ; nucleotide sequences ; regulator genes ; HINFP ; NPAT ; Histone locus body (HLB) ; HiC ; Histone genes ; HLBs ; mRNA ; FLASH ; CASP8AP2 ; LSM10 ; LSM11 ; CDK2 ; CCNE1 ; CCNE2 ; H4 ; TADs ; CTCF ; cHiC ; STR ; DMEM ; BAC ; SC1 ; SC2 ; SC3 ; DR ; IF ; FISH ; TRITC ; FITC ; ChIP-seq ; PCR ; SPRI ; H3K4Me1 ; H3K4Me3 ; H3K27ac ; H3K9Me3 ; H3K27Me3 ; U7snRNP ; ZNF311 ; LINC01623 ; LINC01556 ; TRIM27 ; 3D
Language	English
Dates of publication	2023-07
Publishing place	Elsevier B.V.
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2023.147441
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Article ; Online: Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema.

Schiffers, Caspar / Lundblad, Lennart K A / Hristova, Milena / Habibovic, Aida / Dustin, Christopher M / Daphtary, Nirav / Aliyeva, Minara / Seward, David J / Janssen-Heininger, Yvonne M W / Wouters, Emiel F M / Reynaert, Niki L / van der Vliet, Albert

American journal of physiology. Lung cellular and molecular physiology

2021 Volume 321, Issue 1, Page(s) L144–L158

Abstract: Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity, and impaired innate host defense. One important aspect of innate airway epithelial host defense to nonmicrobial triggers is ... ...

Abstract	Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity, and impaired innate host defense. One important aspect of innate airway epithelial host defense to nonmicrobial triggers is the secretion of alarmins such as IL-33 and activation of type 2 inflammation, which were previously found to depend on activation of the NADPH oxidase (NOX) homolog DUOX1, and redox-dependent signaling pathways that promote alarmin secretion. Here, we demonstrate that normal aging of C57BL/6J mice resulted in markedly decreased lung innate epithelial type 2 responses to exogenous triggers such as the airborne allergen
MeSH term(s)	Acute Lung Injury/etiology ; Acute Lung Injury/metabolism ; Acute Lung Injury/pathology ; Aging/pathology ; Animals ; Dual Oxidases/physiology ; Female ; Inflammation/etiology ; Inflammation/metabolism ; Inflammation/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pulmonary Emphysema/etiology ; Pulmonary Emphysema/metabolism ; Pulmonary Emphysema/pathology ; Respiratory Mucosa/metabolism ; Respiratory Mucosa/pathology
Chemical Substances	Dual Oxidases (EC 1.11.1.-) ; Duox1 protein, mouse (EC 1.6.3.1)
Language	English
Publishing date	2021-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00021.2021
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Zs.A 2749: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Functional assessment of somatic STK11 variants identified in primary human non-small cell lung cancers.

Donnelly, Liam L / Hogan, Tyler C / Lenahan, Sean M / Nandagopal, Gopika / Eaton, Jenna G / Lebeau, Meagan A / McCann, Cai L / Sarausky, Hailey M / Hampel, Kenneth J / Armstrong, Jordan D / Cameron, Margaret P / Sidiropoulos, Nikoletta / Deming, Paula / Seward, David J

Carcinogenesis

2021 Volume 42, Issue 12, Page(s) 1428–1438

Abstract: Serine/Threonine Kinase 11 (STK11) encodes an important tumor suppressor that is frequently mutated in lung adenocarcinoma. Clinical studies have shown that mutations in STK11 resulting in loss of function correlate with resistance to anti-PD-1 ... ...

Abstract	Serine/Threonine Kinase 11 (STK11) encodes an important tumor suppressor that is frequently mutated in lung adenocarcinoma. Clinical studies have shown that mutations in STK11 resulting in loss of function correlate with resistance to anti-PD-1 monoclonal antibody therapy in KRAS-driven non-small cell lung cancer (NSCLC), but the molecular mechanisms responsible remain unclear. Despite this uncertainty, STK11 functional status is emerging as a reliable biomarker for predicting non-response to anti-PD-1 therapy in NSCLC patients. The clinical utility of this biomarker ultimately depends upon accurate classification of STK11 variants. For nonsense variants occurring early in the STK11 coding region, this assessment is straightforward. However, rigorously demonstrating the functional impact of missense variants remains an unmet challenge. Here we present data characterizing four STK11 splice-site variants by analyzing tumor mRNA, and 28 STK11 missense variants using an in vitro kinase assay combined with a cell-based p53-dependent luciferase reporter assay. The variants we report were identified in primary human NSCLC biopsies in collaboration with the University of Vermont Genomic Medicine group. Additionally, we compare our experimental results with data from 22 in silico predictive algorithms. Our work highlights the power, utility and necessity of functional variant assessment and will aid STK11 variant curation, provide a platform to assess novel STK11 variants and help guide anti-PD-1 therapy utilization in KRAS-driven NSCLCs.
MeSH term(s)	AMP-Activated Protein Kinase Kinases/genetics ; AMP-Activated Protein Kinase Kinases/metabolism ; Alternative Splicing ; Biomarkers, Tumor ; CRISPR-Cas Systems ; Carcinoma, Non-Small-Cell Lung/diagnosis ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/mortality ; DNA Mutational Analysis ; Disease Susceptibility ; Gene Editing ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Humans ; Lung Neoplasms/diagnosis ; Lung Neoplasms/genetics ; Lung Neoplasms/mortality ; Mutagenesis, Site-Directed ; Mutation ; Mutation, Missense ; Phosphorylation ; Prognosis ; RNA Splice Sites
Chemical Substances	Biomarkers, Tumor ; RNA Splice Sites ; STK11 protein, human (EC 2.7.11.1) ; AMP-Activated Protein Kinase Kinases (EC 2.7.11.3)
Language	English
Publishing date	2021-11-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603134-1
ISSN	1460-2180 ; 0143-3334
ISSN (online)	1460-2180
ISSN	0143-3334
DOI	10.1093/carcin/bgab104
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