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1.
Genome Med ; 16(1): 91, 2024 Jul 22.
Article in English | MEDLINE | ID: mdl-39034402

ABSTRACT

BACKGROUND: The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. METHODS: In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. RESULTS: PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. CONCLUSIONS: PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex-unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.


Subject(s)
Heterogeneous-Nuclear Ribonucleoprotein Group M , Lung Neoplasms , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Heterogeneous-Nuclear Ribonucleoprotein Group M/metabolism , Heterogeneous-Nuclear Ribonucleoprotein Group M/genetics , Mice , Animals , RNA Splicing , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Mutation , Disease Progression , Protein Binding , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Adenocarcinoma of Lung/metabolism
2.
Nat Commun ; 14(1): 1726, 2023 03 28.
Article in English | MEDLINE | ID: mdl-36977662

ABSTRACT

Mis-sense mutations affecting TP53 promote carcinogenesis both by inactivating tumor suppression, and by conferring pro-carcinogenic activities. We report here that p53 DNA-binding domain (DBD) and transactivation domain (TAD) mis-sense mutants unexpectedly activate pro-carcinogenic epidermal growth factor receptor (EGFR) signaling via distinct, previously unrecognized molecular mechanisms. DBD- and TAD-specific TP53 mutants exhibited different cellular localization and induced distinct gene expression profiles. In multiple tissues, EGFR is stabilized by TAD and DBD mutants in the cytosolic and nuclear compartments respectively. TAD mutants promote EGFR-mediated signaling by enhancing EGFR interaction with AKT via DDX31 in the cytosol. Conversely, DBD mutants maintain EGFR activity in the nucleus, by blocking EGFR interaction with the phosphatase SHP1, triggering c-Myc and Cyclin D1 upregulation. Our findings suggest that p53 mutants carrying gain-of-function, mis-sense mutations affecting two different domains form new protein complexes that promote carcinogenesis by enhancing EGFR signaling via distinctive mechanisms, exposing clinically relevant therapeutic vulnerabilities.


Subject(s)
ErbB Receptors , Tumor Suppressor Protein p53 , Tumor Suppressor Protein p53/metabolism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Signal Transduction , Transcriptional Activation , Phosphorylation
3.
J Pathol ; 259(3): 342-356, 2023 03.
Article in English | MEDLINE | ID: mdl-36573560

ABSTRACT

The relatively quiet mutational landscape of rhabdomyosarcoma (RMS) suggests that epigenetic deregulation could be central to oncogenesis and tumour aggressiveness. Histone variants have long been recognised as important epigenetic regulators of gene expression. However, the role of histone variants in RMS has not been studied hitherto. In this study, we show that histone variant H3.3 is overexpressed in alveolar RMS (ARMS), an aggressive subtype of RMS. Functionally, knockdown of H3F3A, which encodes for H3.3, significantly impairs the ability of ARMS cells to undertake migration and invasion and reduces Rho activation. In addition, a striking reduction in metastatic tumour burden and improved survival is apparent in vivo. Using RNA-sequencing and ChIP-sequencing analyses, we identified melanoma cell adhesion molecule (MCAM/CD146) as a direct downstream target of H3.3. Loss of H3.3 resulted in a reduction in the presence of active marks and an increase in the occupancy of H1 at the MCAM promoter. Cell migration and invasion were rescued in H3F3A-depleted cells through MCAM overexpression. Moreover, we identified G9a, a lysine methyltransferase encoded by EHMT2, as an upstream regulator of H3F3A. Therefore, this study identifies a novel H3.3 dependent axis involved in ARMS metastasis. These findings establish the potential of MCAM as a therapeutic target for high-risk ARMS patients. © 2022 The Pathological Society of Great Britain and Ireland.


Subject(s)
Histones , Rhabdomyosarcoma, Alveolar , Humans , Cell Line, Tumor , Histocompatibility Antigens/genetics , Histocompatibility Antigens/metabolism , Histone-Lysine N-Methyltransferase/genetics , Histones/genetics , Histones/metabolism , Promoter Regions, Genetic , Rhabdomyosarcoma, Alveolar/genetics , Rhabdomyosarcoma, Alveolar/pathology
4.
Cell Rep ; 22(8): 2190-2205, 2018 02 20.
Article in English | MEDLINE | ID: mdl-29466743

ABSTRACT

How are closely related lineages, including liver, pancreas, and intestines, diversified from a common endodermal origin? Here, we apply principles learned from developmental biology to rapidly reconstitute liver progenitors from human pluripotent stem cells (hPSCs). Mapping the formation of multiple endodermal lineages revealed how alternate endodermal fates (e.g., pancreas and intestines) are restricted during liver commitment. Human liver fate was encoded by combinations of inductive and repressive extracellular signals at different doses. However, these signaling combinations were temporally re-interpreted: cellular competence to respond to retinoid, WNT, TGF-ß, and other signals sharply changed within 24 hr. Consequently, temporally dynamic manipulation of extracellular signals was imperative to suppress the production of unwanted cell fates across six consecutive developmental junctures. This efficiently generated 94.1% ± 7.35% TBX3+HNF4A+ human liver bud progenitors and 81.5% ± 3.2% FAH+ hepatocyte-like cells by days 6 and 18 of hPSC differentiation, respectively; the latter improved short-term survival in the Fah-/-Rag2-/-Il2rg-/- mouse model of liver failure.


Subject(s)
Cell Differentiation , Liver/cytology , Pluripotent Stem Cells/cytology , Animals , Animals, Newborn , Biliary Tract/cytology , Biomarkers/metabolism , Bone Morphogenetic Proteins/pharmacology , Cell Differentiation/drug effects , Cyclic AMP-Dependent Protein Kinases/metabolism , Endoderm/cytology , Fibroblast Growth Factors/pharmacology , Gastrointestinal Tract/cytology , Hepatocytes/cytology , Hepatocytes/drug effects , High-Throughput Screening Assays , Humans , Liver/injuries , Liver/pathology , Mice , Pluripotent Stem Cells/drug effects , Signal Transduction , Tretinoin/pharmacology , Wnt Signaling Pathway/drug effects
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