N6-methyladenosine reader YTHDF2 promotes multiple myeloma cell proliferation through EGR1/p21cip1/waf1/CDK2-Cyclin E1 axis-mediated cell cycle transition

Abstract

Multiple myeloma (MM) is the second most common hematological malignancy. N6-methyladenosine (m⁶A) is the most abundant RNA modification. YTH domain-containing family protein 2 (YTHDF2) recognizes m⁶A-cotaining RNAs and accelerates degradation to regulate cancer progression. However, the role of YTHDF2 in MM remains unclear. We investigated the expression levels and prognostic role of YTHDF2 in MM, and studied the effect of YTHDF2 on MM proliferation and cell cycle. The results showed that YTHDF2 was highly expressed in MM and was an independent prognostic factor for MM survival. Silencing YTHDF2 suppressed cell proliferation and caused the G₁/S phase cell cycle arrest. RNA immunoprecipitation (RIP) and m⁶A-RIP (MeRIP) revealed that YTHDF2 accelerated EGR1 mRNA degradation in an m⁶A-dependent manner. Moreover, overexpression of YTHDF2 promoted MM growth via the m⁶A-dependent degradation of EGR1 both in vitro and in vivo. Furthermore, EGR1 suppressed cell proliferation and retarded cell cycle by activating p21^cip1/waf1 transcription and inhibiting CDK2-cyclinE1. EGR1 knockdown could reverse the inhibited proliferation and cell cycle arrest upon YTHDF2 knockdown. In conclusion, the high expression of YTHDF2 promoted MM cell proliferation via EGR1/p21^cip1/waf1/CDK2-cyclin E1 axis-mediated cell cycle transition, highlighting the potential of YTHDF2 as an effective prognostic biomarker and a promising therapeutic target for MM.