TY - JOUR
T1 - Tarbp2 suppresses ubiquitin-proteasomal degradation of hif-1α in breast cancer
AU - Li, Jie Ning
AU - Chen, Pai Sheng
AU - Chiu, Ching Feng
AU - Lyu, Yu Jhen
AU - Lo, Chiao
AU - Tsai, Li Wei
AU - Wang, Ming Yang
N1 - Funding Information:
Funding: This study was supported by the Ministry of Science and Technology, Taiwan (MOST 108-2320-B-006-041-MY3, MOST 110-2320-B-006-059-, MOST 110-2811-B-006-549-, MOST 109-2622-B-002-010, MOST 110-2622-B-002-002, MOST 109-2314-B-002 -048 -MY3, MOST 110-2320-B-038-071), the Department of Surgery, National Taiwan University Hospital, Taiwan (109-S4624), and the Department of Surgical Oncology, National Taiwan University Cancer Center, Taiwan (NTUCCS-110-09).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - TAR (HIV-1) RNA binding protein 2 (TARBP2) is an RNA-binding protein participating in cytoplasmic microRNA processing. Emerging evidence has shown the oncogenic role of TARBP2 in promoting cancer progression, making it an unfavorable prognosis marker for breast cancer. Hypoxia is a hallmark of the tumor microenvironment which induces hypoxia-inducible factor-1α (HIF-1α) for transcriptional regulation. HIF-1α is prone to be rapidly destabilized by the ubiquitination–proteasomal degradation system. In this study, we found that TARBP2 expression is significantly correlated with induced hypoxia signatures in human breast cancer tissues. At a cellular level, HIF-1α protein level was maintained by TARBP2 under either normoxia or hypoxia. Mechanistically, TARBP2 enhanced HIF-1α protein stability through preventing its proteasomal degradation. In addition, downregulation of multiple E3 ligases targeting HIF-1α (VHL, FBXW7, TRAF6) and reduced ubiquitination of HIF-1α were also induced by TARBP2. In support of our clinical findings that TARBP2 is correlated with tumor hypoxia, our IHC staining showed the positive correlation between HIF-1α and TARBP2 in human breast cancer tissues. Taken together, this study indicates the regulatory role of TARBP2 in the ubiquitination–proteasomal degradation of HIF-1α protein in breast cancer.
AB - TAR (HIV-1) RNA binding protein 2 (TARBP2) is an RNA-binding protein participating in cytoplasmic microRNA processing. Emerging evidence has shown the oncogenic role of TARBP2 in promoting cancer progression, making it an unfavorable prognosis marker for breast cancer. Hypoxia is a hallmark of the tumor microenvironment which induces hypoxia-inducible factor-1α (HIF-1α) for transcriptional regulation. HIF-1α is prone to be rapidly destabilized by the ubiquitination–proteasomal degradation system. In this study, we found that TARBP2 expression is significantly correlated with induced hypoxia signatures in human breast cancer tissues. At a cellular level, HIF-1α protein level was maintained by TARBP2 under either normoxia or hypoxia. Mechanistically, TARBP2 enhanced HIF-1α protein stability through preventing its proteasomal degradation. In addition, downregulation of multiple E3 ligases targeting HIF-1α (VHL, FBXW7, TRAF6) and reduced ubiquitination of HIF-1α were also induced by TARBP2. In support of our clinical findings that TARBP2 is correlated with tumor hypoxia, our IHC staining showed the positive correlation between HIF-1α and TARBP2 in human breast cancer tissues. Taken together, this study indicates the regulatory role of TARBP2 in the ubiquitination–proteasomal degradation of HIF-1α protein in breast cancer.
KW - Breast cancer
KW - HIF-1α
KW - TARBP2
KW - Ubiquitinated degradation
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U2 - 10.3390/ijms23010208
DO - 10.3390/ijms23010208
M3 - Article
C2 - 35008634
AN - SCOPUS:85121585482
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 1
M1 - 208
ER -
