The Circadian Clock Gene, Bmal1, Regulates Intestinal Stem Cell Signaling and Represses Tumor Initiation

Autor(es):Mostrar menos -

Stokes, Kyle ^[1] ; Nunes, Malika ^[1] ; Trombley, Chantelle ^[1] ; Flores, Danilo E. F. L. ^[2] ; Wu, Gang ^[2] ; Taleb, Zainab ^[1] ; Alkhateeb, Abedalrhman ^[3] ; Banskota, Suhrid ^[4] ; Harris, Chris ^[5] ; Love, Oliver P. ^[5] ; Khan, I, Waliul ; Rueda, Luis ^[3] ; Hogenesch, John B. ^[2] ; Karpowicz, Phillip ^[1]

Afiliação do(s) autor(es)

^[1] Univ Windsor, Dept Biomed Sci, 410 Sunset Av, Essex 275-2, Windsor, ON N9B 3P4 - Canada

^[2] Cincinnati Childrens Hosp Med Ctr, Div Human Genet & Immunobiol, Cincinnati, OH 45229 - USA

^[3] Univ Windsor, Sch Comp Sci, Windsor, ON - Canada

^[4] I, McMaster Univ, Farncombe Family Digest Hlth Res Inst, Dept Pathol & Mol Med, Hamilton, ON - Canada

^[5] Univ Windsor, Dept Integrat Biol, Windsor, ON - Canada

• Tipo de documento: Artigo Científico
• Fonte: CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY; v. 12, n. 5, p. 1847-1872, 2021.
• Citações Web of Science: 1

Resumo

The loss of circadian rhythms in the intestine leads to aberrant regulation of stem cell signaling pathways and increased tumor initiation. BACKGROUND \& AIMS: Circadian rhythms are daily physio-logical oscillations driven by the circadian clock: a 24-hour transcriptional timekeeper that regulates hormones, inflam-mation, and metabolism. Circadian rhythms are known to be important for health, but whether their loss contributes to colorectal cancer is not known. We tested the nonredundant clock gene Bmal1 in intestinal homeostasis and tumorigenesis, using the Apcmin model of colorectal cancer. METHODS: Bmal1 mutant, epithelium-conditional Bmal1 mutant, and photoperiod (day/night cycle) disrupted mice bearing the Apcmin allele were assessed for tumorigenesis. Tumors and normal nontransformed tissue were characterized. Intestinal organoids were assessed for circadian transcription rhythms by RNA sequencing, and in vivo and organoid assays were used to test Bmal1-dependent proliferation and self-renewal. RESULTS: Loss of Bmal1 or circadian photoperiod increases tumor initiation. In the intestinal epithelium the clock regulates transcripts involved in regeneration and intestinal stem cell signaling. Tumors have no self-autonomous clock function and only weak clock function in vivo. Apcmin clock-disrupted tumors show high Yes-associated protein 1 (Hippo signaling) activity but show low Wnt (Wingless and Int-1) activity. Intestinal organoid assays show that loss of Bmal1 increases self-renewal in a Yes-associated protein 1-dependent manner. CONCLUSIONS: Bmal1 regulates intestinal stem cell pathways, including Hippo signaling, and the loss of circadian rhythms potentiates tumor initiation. (AU)

• Processo FAPESP: 19/04451-3 - Papel do TSC22D3, um fator de transcrição de zíper de leucina induzido por glicocorticóide, no relógio molecular circadiano
• Beneficiário: Danilo Eugênio de França Laurindo Flôres
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado