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A Splicing Factor, PRPF6 Upregulates Oncogenic AR Signaling Pathway in Hepatocellular Carcinoma
49 Pages Posted: 29 Jun 2020
More...Abstract
Background : Androgen receptor (AR) signaling is considered to be crucial for the pathogenesis of hepatocellular carcinoma (HCC) with obvious sexual dimorphism, although anti-androgen treatment has no significant effect on HCC therapy. Androgen receptor splice variants (AR-Vs) possesses a constitutively active function to be essential for HCC progression. The mechanism underlying the modulation of AR/AR-V7 action in HCC is still elusive. Pre-mRNA processing factor 6 (PRPF6) was identified as a coactivator of AR. However, what is the molecular mechanism underlying the modulation function of PRPF6 on AR-mediated transcriptional activity in HCC cells needs to be further clarified.
Methods: We analyzed the regulation of PRPF6 on AR-mediated transactivation and its possible mechanism in HCC cells. The influences of PRPF6 on cell proliferation of HCC was examined in vitro and in vivo.
Findings: Our study demonstrated that PRPF6 interacts with AR/AR-Vs and up-regulates AR/AR-Vs-mediated transcriptional activity even without DHT treatment. Moreover, PRPF6 participates in up-regulating AR itself transcription. PRPF6 or AR is recruited to androgen responsive elements (AREs) region of AR gene. In addition, PRPF6 depletion inhibits cell proliferation in HCC cells and mice xenograft. PRPF6 is highly expressed in HCC, which is positively correlated with poor prognosis.
Interpretation: Our results suggest that PRPF6 as a splicing factor enhances AR itself transcription, thereby co-activating oncogenic AR/AR-Vs actions in HCC.
Funding Statement: This study was supported by National Natural Science Foundation of China (31871286, 81872015, 31701102, 81702800, 81902889), and China Postdoctoral Science Foundation (2019M651164).
Declaration of Interests: None declared.
Ethics Approval Statement: All procedures involved in animal experiments were carried out in compliance with ethical regulations approved by the Animal Ethics Committee of China Medical University.
Keywords: PRPF6; androgen receptor; splicing variants; transcriptional regulation; hepatocellular carcinoma
Suggested Citation: Suggested Citation