ALKBH5-PYCR2 Positive Feedback Loop Promotes Proneural-Mesenchymal Transition Via Proline Synthesis In GBM

Abstract

AlkB homolog 5, RNA demethylase (ALKBH5) is abnormally highly expressed in glioblastoma multiforme (GBM) and is negatively correlated with overall survival in GBM patients. In this study, we found a new mechanism that ALKBH5 and pyrroline-5-carboxylate reductase 2 (PYCR2) formed a positive feedback loop involved in proline synthesis in GBM. ALKBH5 promoted PYCR2 expression and PYCR2-mediated proline synthesis; while PYCR2 promoted ALKBH5 expression through the AMPK/mTOR pathway in GBM cells. In addition, ALKBH5 and PYCR2 promoted GBM cell proliferation, migration, and invasion, as well as proneural-mesenchymal transition (PMT). Furthermore, proline rescued AMPK/mTOR activation and PMT after silencing PYCR2 expression. Our findings reveal an ALKBH5-PYCR2 axis linked to proline metabolism, which plays an important role in promoting PMT in GBM cells and may be a promising therapeutic pathway for GBM.

Emerging Roles and Mechanisms of RNA Modifications in Neurodegenerative Diseases and Glioma

“…ALKBH5 overexpression in glioblastoma stem cells contributes to increased resistance to radiation and enhanced invasive capabilities, and its activity is regulated by EGFR signaling, impacting ferroptosis through m6A modulation [ 148 , 149 ]. ALKBH5 also promotes PYCR2 expression, influencing glioma cell proliferation, migration, and PMT [ 150 ]. The regulation of ALKBH5 by USP36 underscores its role in glioblastoma progression and sensitivity to TMZ [ 151 ].…”

Subtype Transdifferentiation in Human Cancer: The Power of Tissue Plasticity in Tumor Progression

“…Similarly, pyrroline-5-carboxylate reductase 2 (PYCR2), which is involved in proline synthesis together with the AlkB homolog 5 RNA demethylase (ALKBH5), promotes PMT, cell proliferation, migration, and invasion in GBM [92].…”