A positive feedback circuit between RN7SK snRNA and m⁶A readers is essential for tumorigenesis

N⁶-Methyladenosine (m⁶A) RNA modification, methylation at the N6 position of adenosine, plays critical roles in tumorigenesis. m⁶A readers recognize m⁶A modifications and thus act as key executors for the biological consequences of RNA methylation. However, knowledge about the regulatory mechanism(s) of m⁶A readers is extremely limited. In this study, RN7SK was identified as a small nuclear RNA that interacts with m⁶A readers. m⁶A readers recognized and facilitated secondary structure formation of m⁶A-modified RN7SK, which in turn prevented m⁶A reader mRNA degradation from exonucleases. Thus, a positive feedback circuit between RN7SK and m⁶A readers is established in tumor cells. From findings on the interaction with RN7SK, new m⁶A readers, such as EWS RNA binding protein 1 (EWSR1) and KH RNA binding domain containing, signal transduction-associated 1 (KHDRBS1), were identified and shown to boost Wnt/β-catenin signaling and tumorigenesis by suppressing translation of Cullin1 (CUL1). Moreover, several Food and Drug Administration-approved small molecules were demonstrated to reduce RN7SK expression and inhibit tumorigenesis. Together, these findings reveal a common regulatory mechanism of m⁶A readers and indicate that targeting RN7SK has strong potential for tumor treatment.