The C-Terminal Acidic Tail Modulates the Anticancer Properties of HMGB1.

International journal of molecular sciences 2022 Jul 17

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Energy metabolism reprogramming was recently listed as a hallmark of cancer. In this process, the switch from pyruvate kinase isoenzyme type M1 to pyruvate kinase isoenzyme type M2 (PKM2) is believed to play a crucial role. Interestingly, the activity of the active form of PKM2 can efficiently be inhibited by the high-mobility group box 1 (HMGB1) protein, leading to a rapid blockage of glucose-dependent aerobic respiration and cancer cell death. HMGB1 is a member of the HMG protein family. It contains two DNA-binding HMG-box domains and an acidic C-terminal tail capable of positively or negatively modulating its biological properties. In this work, we report that the deletion of the C-terminal tail of HMGB1 increases its activity towards a large panel of cancer cells without affecting the viability of normal immortalized fibroblasts. Moreover, in silico analysis suggests that the truncated form of HMGB1 retains the capacity of the full-length protein to interact with PKM2. However, based on the capacity of the cells to circumvent oxidative phosphorylation inhibition, we were able to identify either a cytotoxic or cytostatic effect of the proteins. Together, our study provides new insights in the characterization of the anticancer activity of HMGB1.

Citation

Chloé Borde, Clémentine Dillard, Aurore L'Honoré, Frédérique Quignon, Marion Hamon, Christophe H Marchand, Roberta Soares Faccion, Maurício G S Costa, Elodie Pramil, Annette K Larsen, Michèle Sabbah, Stéphane D Lemaire, Vincent Maréchal, Alexandre E Escargueil. The C-Terminal Acidic Tail Modulates the Anticancer Properties of HMGB1. International journal of molecular sciences. 2022 Jul 17;23(14)