m6A-dependent 7-dehydrocholesterol reductase facilitates bladder cancer metastasis via cAMP/PKA/FAK axis

Cholesterol homeostasis dysregulation appears in multiple tumors. However, the specific processes that cause abnormal cholesterol metabolism to affect the invasion and metastasis of bladder cancer (BC) are still unclear. In our investigation, we found a notable rise in the expression of 7-dehydrocholesterol reductase (DHCR7), a key enzyme involved in the synthesis of cholesterol, within BC tissues in comparison to normal tissues and correlated to the invasion and metastasis of BC. This elevated expression of DHCR7 in BC was attributed to the decreased degradation of mRNA mediated by YTHDF2. We discovered that DHCR7 plays a role in promoting bladder cancer invasion and metastasis by activating the cAMP-PKA-FAK pathway. Specifically, DHCR7 was found to increase the levels of cAMP by enhancing cholesterol content in lipid rafts, thereby facilitating the transduction of signaling pathways mediated by cAMP receptors. Additionally, DHCR7 was found to enhance the cAMP signaling pathway by reducing the concentration of 7-DHC and promoting the transcription of GIPR. Overall, our findings demonstrated that DHCR7 plays a crucial role in BC invasion and metastasis by modulating cholesterol synthesis and cAMP signaling pathways. Furthermore, AY9944, which acts as an inhibitor of DHCR7, shows promise as a viable therapeutic strategy for the suppression of invasion and metastasis in BC.