HKDC1 functions as a glucose sensor and promotes metabolic adaptation and cancer growth via interaction with PHB2.

Cell Death Differ

State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.

Published: December 2024

AI Article Synopsis

  • Glucose sensing in tumors is vital for cancer progression, and HKDC1, a key hexokinase associated with poor outcomes, acts as a glucose sensor that adjusts its stability based on glucose levels in the environment.
  • The specific region (amino acids 751-917) of HKDC1 has a crucial role in sensing glucose, with Ser896 being important for regulating its stability and thus influencing cancer cell responses to glucose availability.
  • By inhibiting prohibitin 2 (PHB2) and facilitating the expression of oncogenic molecules, HKDC1 promotes tumor growth; targeting HKDC1 could offer a new therapeutic strategy to combat cancer.

Article Abstract

Glucose sensing and metabolic adaptation to glucose availability in the tumor microenvironment are critical for cancer development. Here we show that HKDC1, a hexokinase highly expressed in cancer associated with poor prognosis, functions as a glucose sensor that alters its stability in response to environmental glucose. The glucose-sensing domain is located between amino acids 751-917, with Ser896 as a key residue that regulates HKDC1 stability by affecting Lys620 ubiquitination. This sensing mechanism enables cellular adaptation to glucose starvation by promoting mitochondrial fatty acid utilization. Furthermore, HKDC1 promotes tumor growth by sequestering prohibitin 2 (PHB2) to disable its suppressive effect on SP1, thus promoting the expression of pro-oncogenic molecules. Abrogation of HKDC1 by genetic knockout or by glucose depletion releases PHB2, leading to suppression of cancer cell proliferation and inhibition of tumor growth. Our study reveals a previously unrecognized role of HKDC1 in glucose sensing and metabolic adaptation, and identifies HKDC1 as a potential therapeutic target.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11618360PMC
http://dx.doi.org/10.1038/s41418-024-01392-5DOI Listing

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