KIAA1429 and AlkB Homolog 5 Regulate Bladder Cancer Progression via N6-Methyladenosine-Dependent Modulation of Sonic Hedgehog Signaling

Abstract

N⁶-methyladenosine (m⁶A) modification plays a pivotal role in cancer progression, yet its regulatory mechanisms in bladder cancer (BCa) remain poorly understood. This study investigates the functions of two key m⁶A regulators-α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) and KIAA1429-in modulating BCa cell behavior. Expression levels of ALKBH5, KIAA1429, and Sonic Hedgehog (SHH) were examined in BCa tissues and adjacent normal tissues. Functional assays, including methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR), RNA immunoprecipitation (RIP), and RNA stability assessments, were performed in J82 BCa cells to explore the underlying mechanisms. Results revealed that KIAA1429 was significantly upregulated in BCa and promoted cell proliferation, migration, and invasion by enhancing m⁶A modification and stabilizing SHH mRNA, leading to activation of the Hedgehog signaling pathway. In contrast, ALKBH5, which was downregulated in BCa, acted as an m⁶A demethylase that destabilized SHH mRNA and attenuated Hedgehog pathway activity, thereby counteracting the oncogenic effects of KIAA1429. Moreover, overexpression of SHH reversed the inhibitory effects induced by KIAA1429 knockdown, confirming its role as a downstream effector. In conclusion, ALKBH5 and KIAA1429 exert opposing regulatory effects on BCa progression via m⁶A-mediated modulation of SHH expression and Hedgehog signaling. These findings highlight SHH mRNA methylation as a central mechanism in BCa malignancy and identify ALKBH5 and KIAA1429 as potential therapeutic targets.

Keywords: ALKBH5; Hedgehog signaling; KIAA1429; bladder cancer; m6A modification.