The fat mass and obesity-associated protein (FTO) is an N6-Methyladenosine (m6A) demethylase, which has been revealed to play critical roles in tumorigenesis. However, its role in the development and progression of prostate cancer (PCa) remains poorly understood. Here, we aimed to investigate the function and clinical relevance of FTO in PCa. Our results demonstrated that FTO was notably downregulated in PCa tissues compared with the paired normal tissues. In addition, the decreased expression of FTO was correlated with poor prognosis of PCa. Functional experiments showed that depletion of FTO promoted the proliferation and metastasis of PCa both in vitro and in vivo. Conversely, ectopic expression of FTO exhibited the opposite effects. Combined with RNA-sequencing, MeRIP-RT-qPCR, and mRNA stability assays indicated chloride intracellular channel 4(CLIC4) was a functional target of FTO-mediated m6A modification. FTO depletion significantly increased the m6A level of CLIC4 mRNA and then reduced the mRNA stability. In conclusion, our findings suggest that FTO suppresses PCa proliferation and metastasis through reducing the degradation of CLIC4 mRNA in an m6A dependent manner. FTO may be used as a promising novel therapeutic target and prognostic evaluation biomarker for PCa.

Prostate cancer (PCa) patients with bone metastasis commonly exhibit osteoblastic-type and have an extremely poor prognosis. Exosomes derived from tumor cells possess biological significance and can mediate intercellular communication in the tumor microenvironment. Long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) is implicated in tumorigenesis and the development of PCa, but the precise roles of SNHG1 in the regulation of bone homeostasis remain elusive. Herein, we aimed to investigate the underlying mechanisms by which exosomes-encapsulated SNHG1 affects the bone metastasis of PCa. Our findings revealed that SNHG1 was overexpressed in PCa tissues, highly enriched in PCa cell-derived exosomes, and positively correlated with bone metastasis. Besides, SNHG1 shuttled by PCa-derived exosomes could be transferred into osteoblast cells, where SNHG1 exerted inductive properties in osteogenic differentiation. Gain- and loss-of-functional experiments demonstrated that exosomal SNHG1 facilitated the activity of alkaline phosphatase and mineralization of extracellular matrix. Moreover, in vivo experimentation showed that knockdown of exosomal SNHG1 suppressed bone metastasis of PCa cells. Mechanistic investigations revealed that exosomal SNHG1, transmitted to osteoblast cells, physically binds to YBX1 and leads to the shift of YBX1 into the nucleus, then enhances MMP16 transcription and increases the amount of protein translation, ultimately resulting in PCa bone metastasis. In conclusion, our data highlight that PCa-derived exosomes-loaded SNHG1 mediated osteogenesis through the SNHG1/YBX1/MMP16 axis. SNHG1 may serve as a potential diagnostic marker and therapeutic target for bone metastasis in PCa.