title: The role of Runx2 in facilitating autophagy in metastatic breast cancer cells.
abstract: Breast cancer metastases cause significant patient mortality. During metastases, cancer cells use autophagy, a catabolic process to recycle nutrients via lysosomal degradation, to overcome nutritional stress for their survival. The Runt-related transcription factor, Runx2, promotes cell survival under metabolic stress, and regulates breast cancer progression and bone metastases. Here, we identify that Runx2 enhances autophagy in metastatic breast cancer cells. We defined Runx2 function in cellular autophagy by monitoring microtubule-associated protein light chain (LC3B-II) levels, an autophagy-specific marker. The electron and confocal microscopic analyses were utilized to identify alterations in autophagic vesicles. The Runx2 knockdown cells accumulate LC3B-II protein and autophagic vesicles due to reduced turnover. Interestingly, Runx2 promotes autophagy by enhancing trafficking of LC3B vesicles. Our mechanistic studies revealed that Runx2 promotes autophagy by increasing acetylation of α-tubulin sub-units of microtubules. Inhibiting autophagy decreased cell adhesion and survival of Runx2 knockdown cells. Furthermore, analysis of LC3B protein in clinical breast cancer specimens and tumor xenografts revealed significant association between high Runx2 and low LC3B protein levels. Our studies reveal a novel regulatory mechanism of autophagy via Runx2 and provide molecular insights into the role of autophagy in metastatic cancer cells.
authors.affiliation: Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois.
authors.forename: Manish
authors.initials: M
authors.lastname: Tandon
authors.affiliation: Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois.
authors.forename: Ahmad H
authors.initials: AH
authors.lastname: Othman
authors.affiliation: Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois.
authors.forename: Vivek
authors.initials: V
authors.lastname: Ashok
authors.affiliation: University of Vermont Cancer Center and Department of Biochemistry, Larner College of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.affiliation: Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois.
authors.forename: Jitesh
authors.identifier: http://orcid.org/0000-0003-2625-137X
authors.initials: J
authors.lastname: Pratap
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D014404:Tubulin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050659:Core Binding Factor Alpha 1 Subunit; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; C493709:RUNX2 protein, human; D014404:Tubulin; D002738:Chloroquine
keywords: LC3B; Runx2; autophagy; breast cancer; metastasis; α-tubulin