TY  - JOUR
A1  - Lee, Hong-Jen
A1  - Li, Chien-Feng
A1  - Ruan, Diane
A1  - He, Jiabei
A1  - Montal, Emily D.
A1  - Lorenz, Sonja
A1  - Girnun, Geoffrey D.
A1  - Chan, Chia-Hsin
T1  - Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion
T2  - Nature Communications
N2  - Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.
KW  - cancer
KW  - cancer metabolism
KW  - molecular biology
Y1  - 2019
UR  - https://opus.bibliothek.uni-wuerzburg.de/opus4-wuerzburg/frontdoor/index/index/docId/23644
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-236445
VL  - 10
ER  -