Transketolase promotes osteosarcoma progression through the YY1-PAK4 axis

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Osteosarcoma is a challenging adolescent bone cancer with high metastatic potential and genetic heterogeneity.
• Tumor metabolism is a consistent vulnerability, offering a therapeutic target.
• Transketolase (TKT), a pentose phosphate pathway enzyme, is upregulated in various cancers.

Purpose of the Study:

• To investigate the role of Transketolase (TKT) in osteosarcoma proliferation.
• To elucidate the molecular mechanism by which TKT promotes osteosarcoma.
• To develop a targeted therapeutic strategy against osteosarcoma.

Main Methods:

• Investigated TKT's non-metabolic role in osteosarcoma cell proliferation.
• Identified TKT's direct binding to Yin Yang 1 (YY1) at specific amino acid residues.
• Assessed the impact of TKT-YY1 interaction on P21 activated kinase 4 (PAK4) expression and PI3K-Akt signaling.
• Designed and tested a peptide inhibitor (YY1-PEP) in vitro and in vivo.

Main Results:

• TKT non-metabolically promotes osteosarcoma cell proliferation.
• TKT directly binds to YY1 (residues 201-228), enhancing YY1 binding to the PAK4 promoter.
• This interaction leads to increased PAK4 expression and PI3K-Akt pathway activation.
• YY1-PEP demonstrated significant anti-osteosarcoma effects in preclinical models.

Conclusions:

• TKT is a key driver of osteosarcoma progression through a non-metabolic pathway involving YY1 and PAK4.
• Targeting the TKT-YY1 interaction with YY1-PEP represents a promising therapeutic strategy for osteosarcoma.