PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells.
Dysfunctional clock signaling is observed in a variety of pathological conditions. Many members of the clock gene family are upregulated in tumor cells. Here, we explored the consequences of a commonly disrupted signaling pathway in head and neck cancer on the regulation of circadian clock genes. PTEN is a key molecular controller of the PI3K signaling, and loss of PTEN function is often observed in a variety of cancers. Our main goal was to determine whether PTEN regulates circadian clock signaling. We found that oxidation-driven loss of PTEN function resulted in the activation of mTOR signaling and activation of the core clock protein BMAL1 (also known as ARNTL). The PTEN-induced BMAL1 upregulation was further confirmed using small interference RNA targeting PTEN, and in vivo conditional depletion of PTEN from the epidermis. We observed that PTEN-driven accumulation of BMAL1 was mTOR-mediated and that administration of Rapamycin, a specific mTOR inhibitor, resulted in in vivo rescue of normal levels of BMAL1. Accumulation of BMAL1 by deletion of PER2, a Period family gene, was also rescued upon in vivo administration of mTOR inhibitor. Notably, BMAL1 regulation requires mTOR regulatory protein Raptor and Rictor. These findings indicate that mTORC1 and mTORC2 complex plays a critical role in controlling BMAL1, establishing a connection between PI3K signaling and the regulation of circadian rhythm, ultimately resulting in deregulated BMAL1 in tumor cells with disrupted PI3K signaling.
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Department of Clinical Analysis, Toxicology and Bromatology, School of Pharmacy, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Camila S
CS
Matsumoto
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Luciana O
LO
Almeida
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Department of Oral Pathology, School of Dentistry, University of Sao Paulo, SP, Brazil.
Douglas M
DM
Guimarães
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Manoela D
MD
Martins
Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.|Center for Organogenesis, University of Michigan, Ann Arbor, MI, USA.
Petros
P
Papagerakis
Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.|Department of Otolaryngology, Medical School, University of Michigan, Ann Arbor, MI, USA.
Silvana
S
Papagerakis
Department of Clinical Analysis, Toxicology and Bromatology, School of Pharmacy, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
Andreia M
AM
Leopoldino
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Rogerio M
RM
Castilho
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Cristiane H
CH
Squarize
D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D002940:Circadian Rhythm; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D020123:Sirolimus / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D056930:ARNTL Transcription Factors; D010100:Oxygen; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C538960:BMAL1 protein, human; C546842:MTOR protein, human; C494929:PTEN protein, human
head and neck cancer; oral cancer