Insights into a novel nuclear function for Fascin in the regulation of the amino-acid transporter SLC3A2.
Fascin 1 (FSCN1) is a cytoskeleton-associated protein recognized to function primarily in the regulation of cytoskeleton structure and formation of plasma membrane protrusions. Here we report a novel nuclear function for Fascin 1. Biochemical studies and genome wide localization using ChIP-seq identified phosphorylated Fascin 1 (pFascin) in complexes associated with transcription and that it co-localizes with histone H3 Lys4 trimethylation (H3K4me3) on chromatin. Gene expression profiling identified genes affected by Fascin 1 including SLC3A2, a gene encoding for a plasma membrane transporter that regulates intracellular amino acid levels. RbBP5, a subunit of the H3K4 histone methyltransferase (HMT) complex was found to interact with Fascin 1 supporting its role in H3K4me3 establishment at target genes. Moreover, we show that changes to SLC3A2 levels affect amino acid-mediated mTORC1 activation. These results reveal that Fascin 1 has a yet undiscovered nuclear function as an epigenetic modulator of genes essential for amino acid metabolism.
Departments of Medicine, Oncology, Pharmacology and Therapeutics , Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste Catherine, Montreal, Quebec, H3T 1E2, Canada.
Amine
A
Saad
Departments of Medicine, Oncology, Pharmacology and Therapeutics , Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste Catherine, Montreal, Quebec, H3T 1E2, Canada.
Krikor
K
Bijian
Departments of Medicine, Oncology, Pharmacology and Therapeutics , Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste Catherine, Montreal, Quebec, H3T 1E2, Canada.
Dinghong
D
Qiu
Departments of Medicine, Oncology, Pharmacology and Therapeutics , Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste Catherine, Montreal, Quebec, H3T 1E2, Canada.|Otolaryngology-Head and Neck Surgery, Faculty of Medicine, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada.
Sabrina Daniela
SD
da Silva
Departments of Medicine, Oncology, Pharmacology and Therapeutics , Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste Catherine, Montreal, Quebec, H3T 1E2, Canada.
Maud
M
Marques
Departments of Medicine, Oncology, Pharmacology and Therapeutics , Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste Catherine, Montreal, Quebec, H3T 1E2, Canada.
Chia-Hao
CH
Chang
Maisonneuve-Rosemont Hospital, Research Center, University of Montreal, Immunology and Oncology, Montreal, Quebec, H1T 2M4, Canada.
Hassan
H
Nassour
Maisonneuve-Rosemont Hospital, Research Center, University of Montreal, Immunology and Oncology, Montreal, Quebec, H1T 2M4, Canada.
Dindial
D
Ramotar
Departments of Laboratory Medicine and Pathology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.
Sambasivarao
S
Damaraju
Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada.
John
J
Mackey
Departments of Pathology &Laboratory Medicine and Oncology, Southern Alberta Cancer Institute, University of Calgary, Alberta, Canada.
Tarek
T
Bismar
Departments of Medicine, Oncology, Pharmacology and Therapeutics , Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste Catherine, Montreal, Quebec, H3T 1E2, Canada.
Michael
M
Witcher
Departments of Medicine, Oncology, Pharmacology and Therapeutics , Segal Cancer Centre and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste Catherine, Montreal, Quebec, H3T 1E2, Canada.|Otolaryngology-Head and Neck Surgery, Faculty of Medicine, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada.
Moulay A
MA
Alaoui-Jamali
D001943:Breast Neoplasms / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C502658:FSCN1 protein, human; D027282:Fusion Regulatory Protein 1, Heavy Chain; D006657:Histones; D008840:Microfilament Proteins; D009687:Nuclear Proteins; C470552:RBBP5 protein, human; C545989:SLC3A2 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases