Androgen-Responsive Oncogenic lncRNA RP11-1023L17.1 Enhances c-Myc Protein Stability in Prostate Cancer

Abstract

Long noncoding RNAs (lncRNAs) have been found as novel participants in the pathophysiology of prostate cancer (PCa), which is predominantly regulated by androgen and its receptor. The biological function of androgen-responsive lncRNAs remains poorly understood. Here, we identified that lncRNA RP11-1023L17.1, which is highly expressed in PCa. RP11-1023L17.1 expression, can be directly repressed by the androgen receptor in PCa cells. RP11-1023L17.1 depletion inhibited the proliferation, migration, and cell cycle progression, and promoted the apoptosis of PCa cells, indicating that RP11-1023L17.1 acts as an oncogene in PCa cells. Microarray results revealed that RP11-1023L17.1 depletion downregulated the c-Myc transcription signature in PCa cells. RP11-1023L17.1 depletion-induced cellular phenotypes can be overcome by ectopically overexpressed c-Myc. Mechanistically, RP11-1023L17.1 represses FBXO32 mRNA expression, thereby enhancing c-Myc protein stability by blocking FBXO32-mediated c-Myc degradation. Our findings reveal the previously unrecognized roles of RP11-1023L17.1 in c-Myc-dependent PCa tumorigenesis.

Long Non-Coding RNAs as “MYC Facilitators”

“…Specific cancers provide examples of these effects. In prostate cancer, lncRNA RP11-1023L17.1 acts as an oncogene, regulating MYC’s transcriptional signature, and its depletion leads to the downregulation of MYC-dependent oncogenic features in a tumor [ 102 ]. In non-small cell lung cancer, lncRNA HIF1A-As2 forms a positive feedback loop with MYC, driving cell proliferation and tumor metastasis [ 103 ].…”

DNMT1‐mediated regulating on FBXO32 promotes the progression of glioma cells through the regulation of SKP1 activity

“…4 The F-box protein family members are known to regulate diverse biological processes, including cell cycle progression, apoptosis, cell migration, and protein degradation. 5,6 In the context of tumorigenesis, FBXO32 has been extensively investigated, displaying diverse roles depending on the tumor type. In certain cases, FBXO32 has been identified as a tumor suppressor, associated with the inhibition of tumor growth and metastasis.…”

“…7,8 Notably, elevated FBXO32 expression has been correlated with improved overall survival and reduced tumor invasiveness in breast cancer, colorectal cancer, and prostate cancer, among others. 5,9,10 Mechanistically, FBXO32 may exert its tumor-suppressive effects through the modulation of crucial tumor suppressor genes, restraining tumor cell proliferation, migration, and invasion. Conversely, in certain muscle-related tumors and possibly other contexts, FBXO32 has been implicated as an oncogenic factor, promoting tumorigenesis.…”

“…One such potential candidate is the F‐box protein 32 (FBXO32), also known as Murf1 (Muscle‐specific RING Finger Protein 1), belongs to the F‐box protein family and plays a pivotal role in the ubiquitin‐proteasome system, acting as an adaptor protein that facilitates substrate recognition and subsequent ubiquitination for proteasomal degradation 4 . The F‐box protein family members are known to regulate diverse biological processes, including cell cycle progression, apoptosis, cell migration, and protein degradation 5,6 . In the context of tumorigenesis, FBXO32 has been extensively investigated, displaying diverse roles depending on the tumor type.…”

“…In certain cases, FBXO32 has been identified as a tumor suppressor, associated with the inhibition of tumor growth and metastasis 7,8 . Notably, elevated FBXO32 expression has been correlated with improved overall survival and reduced tumor invasiveness in breast cancer, colorectal cancer, and prostate cancer, among others 5,9,10 . Mechanistically, FBXO32 may exert its tumor‐suppressive effects through the modulation of crucial tumor suppressor genes, restraining tumor cell proliferation, migration, and invasion.…”