PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to As2O3 by stabilizing oncoprotein PML-RARα.

Abstract

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the oncoprotein PML-RARα, which can be treated with arsenic trioxide (As2O3) or/and all-trans retinoic acid. The protein arginine methyltransferase 5 (PRMT5) is involved in tumorigenesis. However, little is known about the biological function and therapeutic potential of PRMT5 in APL. Here, we show that PRMT5 is highly expressed in APL patients. PRMT5 promotes APL by interacting with PML-RARα and suppressing its ubiquitination and degradation. Mechanistically, PRMT5 attenuates the interaction between PML-RARα and its ubiquitin E3 ligase RNF4 by methylating RNF4 at Arg164. Notably, As2O3 treatment triggers the dissociation of PRMT5 from PML nuclear bodies, attenuating RNF4 methylation and promoting RNF4-mediated PML-RARα ubiquitination and degradation. Moreover, knockdown of PRMT5 and pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 significantly inhibit APL cells growth. The combination of EPZ015666 with As2O3 shows synergistic effects on As2O3-induced differentiation of bone marrow cells from APL mice, as well as on apoptosis and differentiation of primary APL cells from APL patients. These findings provide mechanistic insight into the function of PRMT5 in APL pathogenesis and demonstrate that inhibition of PRMT5, alone or in combination with As2O3, might be a promising therapeutic strategy against APL.

• Authors: Xinping Huang, Yongfeng Yang, Dan Zhu, Yan Zhao, Min Wei, Ke Li, Hong-Hu Zhu, Xiaofeng Zheng
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 79 Issue 6 Pg. 319 (May 27 2022) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 35622143 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Chemical References

• Antineoplastic Agents
• GSK3235025
• Isoquinolines
• Nuclear Proteins
• Oncogene Proteins, Fusion
• Pyrimidines
• RNF4 protein, human
• Transcription Factors
• promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
• PRMT5 protein, human
• Protein-Arginine N-Methyltransferases
• Arsenic Trioxide

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Arsenic Trioxide (pharmacology, therapeutic use)
• Cell Line, Tumor (drug effects)
• Drug Resistance, Neoplasm (genetics, physiology)
• Humans
• Isoquinolines (pharmacology, therapeutic use)
• Leukemia, Promyelocytic, Acute (drug therapy, genetics, metabolism, pathology)
• Methylation
• Mice
• Nuclear Proteins (genetics, metabolism)
• Oncogene Proteins, Fusion (genetics, metabolism, therapeutic use)
• Protein-Arginine N-Methyltransferases (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (pharmacology, therapeutic use)
• Transcription Factors (genetics, metabolism)
• Ubiquitination