HEATR1 deficiency promotes pancreatic cancer proliferation and gemcitabine resistance by up-regulating Nrf2 signaling

Autor: Keke Wang, Yaxin Chen, Yang Zhou, Rui Wang, Tao Li, Rong Hu, Mengran Cao, Mengdi Yang, Yunjiang Zhou
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
PDAC
pancreatic ductal adenocarcinoma
Clinical Biochemistry
HEATR1
Gemcitabine resistance
Nrf2
nuclear factor erythroid 2-related factor 2
Deoxycytidine
Biochemistry
0302 clinical medicine
Cytotoxic T cell
SQSTM1
sequestosome 1
lcsh:QH301-705.5
HO-1
heme oxygenase-1
chemistry.chemical_classification
education.field_of_study
Gene knockdown
lcsh:R5-920
Kelch-Like ECH-Associated Protein 1
RNA-Binding Proteins
mRNA
messenger RNA
Amino acid
Keap1
Kelch-like ECH-associated protein 1
shRNA
short hairpin RNA
HEATR1
human HEAT repeat-containing protein 1
lcsh:Medicine (General)
Research Paper
NF-E2-Related Factor 2
qRT-PCR
quantitative reverse transcription-PCR
Biology
Nrf2
Minor Histocompatibility Antigens
03 medical and health sciences
Sequestosome 1
Cell Line
Tumor
Pancreatic cancer
NQO1
NAD(P)H quinone oxidoreductase 1
medicine
Humans
education
Cell Proliferation
Organic Chemistry
medicine.disease
Gemcitabine
KEAP1
Pancreatic Neoplasms
030104 developmental biology
chemistry
lcsh:Biology (General)
Cancer research
030217 neurology & neurosurgery
Nrf2 signaling
Zdroj: Redox Biology, Vol 29, Iss, Pp-(2020)
Redox Biology
ISSN: 2213-2317
Popis: The human HEAT repeat-containing protein 1 (HEATR1), consisting of 2144 amino acids, is a member of the UTP10 family and contains one HEAT repeat at its C-terminal. HEATR1 has been reported to regulate cytotoxic T lymphocytes and rRNA synthesis, while its functions in tumors are poorly understood. Here, we found that HEATR1 competed with Keap1 for binding to p62/sequestosome 1 (SQSTM1), resulted in up-regulation of Keap1, which then inhibited Nrf2 signaling in pancreatic cancer cells. HEATR1 knockdown enhanced proliferation and gemcitabine resistance of pancreatic cancer cells. Moreover, HEATR1 deficiency significantly improved xenografts growth and led to gemcitabine resistance in pancreatic cancer cell-derived xenografts through up-regulating Nrf2 signaling. By analyzing tumor tissue samples from pancreatic cancer patients, we found that low expression of HEATR1 was closely correlated with poor prognosis and clinicopathological features. Collectively, we suggest that HEATR1 deficiency promotes proliferation and gemcitabine resistance of pancreatic cancer through up-regulating Nrf2 signaling, indicating that HEATR1 may be a promising therapeutic target for pancreatic cancer.
Highlights • HEATR1 inhibited Nrf2 signaling in pancreatic cancer cells. • HEATR1 inhibited Nrf2 signaling through competing with Keap1 for p62 binding in pancreatic cancer cells. • HEATR1 deficiency promoted pancreatic cancer proliferation and gemcitabine resistance by up-regulating Nrf2 signaling.
Databáze: OpenAIRE
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