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KMT2C inactivation leads to PTEN downregulation and tolerance to DNA damage during cell cycle progression

Citation:

Rampias T, Goutas A, Karagiannis D, Kanaki Z, Makri A, Hoxhallari L, Koukouzeli FE, Paraskevopoulou V, Tsouraki D, Paschalidis N, Avgeris M, Scorilas A, Klinakis A. KMT2C inactivation leads to PTEN downregulation and tolerance to DNA damage during cell cycle progression. NPJ Precision Oncology 2025;9:336.

Abstract:

Uncontrolled proliferation, resistance to apoptosis, inability to maintain genome integrity, and, recently, epigenetic reprogramming are all hallmarks of cancer. A number of gene expression and cell signaling networks control these-often-interconnected processes, while the study of their deregulation is in the forefront of cancer research for decades. Here we present data from cells and patients indicating that KMT2C, one of the most frequently mutated proteins in solid malignancies, is involved in all these processes. Its loss, a bad prognosis marker in bladder cancer, is associated with activation of the PI3K/PDK/AKT oncogenic/antiapoptotic axis, and tolerance to DNA damage during cell cycle progression. On the other hand, these cells suffer from mitotic stress that can be therapeutically exploited. Treatment with a PLK1 inhibitor showed high efficacy in vivo, and was associated with mitotic catastrophe and cellular senescence, providing evidence that targeting genes that promote mitotic progression could be a promising therapeutic approach in the subset of tumors with KMT2C loss.

Notes:

Rampias, TheodorosGoutas, AndreasKaragiannis, DimitrisKanaki, ZoiMakri, AntigoniHoxhallari, LorenaKoukouzeli, Fotini EParaskevopoulou, VarvaraTsouraki, DimitraPaschalidis, NikolaosAvgeris, MargaritisScorilas, AndreasKlinakis, Apostoloseng472-EpiNotch/Hellenic Foundation for Research and Innovation/3218-EpiCS/Hellenic Foundation for Research and Innovation/England2025/10/29 06:28NPJ Precis Oncol. 2025 Oct 28;9(1):336. doi: 10.1038/s41698-025-01101-6.