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

by Selleckchem | Jun 25 2023

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

Comments:

The passage you provided describes a study on the role of protein arginine methyltransferase 5 (PRMT5) in acute promyelocytic leukemia (APL) and its potential as a therapeutic target. Here's a summary of the main findings:

PRMT5 expression: The researchers observed high levels of PRMT5 expression in APL patients, suggesting its involvement in APL development.

Interaction with PML-RARα: PRMT5 was found to interact with the oncoprotein PML-RARα, which is known to drive APL. This interaction led to the suppression of PML-RARα's ubiquitination (a process that marks proteins for degradation) and degradation.

Mechanism of action: PRMT5 achieved the suppression of PML-RARα ubiquitination by methylating a protein called RNF4 at a specific site (Arg164). This methylation reduced the interaction between PML-RARα and RNF4, hindering the ubiquitin-mediated degradation of PML-RARα.

As2O3 treatment: Arsenic trioxide (As2O3) is a known treatment for APL. The researchers found that As2O3 caused the dissociation of PRMT5 from PML nuclear bodies. This dissociation resulted in reduced RNF4 methylation and promoted RNF4-mediated ubiquitination and degradation of PML-RARα.

Inhibition of PRMT5: Both knockdown of PRMT5 and treatment with the specific inhibitor EPZ015666 significantly inhibited the growth of APL cells. This suggests that inhibiting PRMT5 could be a promising therapeutic approach for APL.

Combination therapy: Combining EPZ015666 with As2O3 showed synergistic effects on As2O3-induced differentiation of bone marrow cells from APL mice. It also enhanced apoptosis (cell death) and differentiation of primary APL cells from APL patients. This suggests that combining PRMT5 inhibition with As2O3 treatment may be an effective therapeutic strategy against APL.

These findings provide important insights into the role of PRMT5 in APL pathogenesis and highlight the potential of targeting PRMT5, either alone or in combination with As2O3, as a promising therapeutic approach for APL.