Downregulation of nc886 contributes to prostate cancer cell invasion and TGFβ1-induced EMT

Ronghui Yang; Lingkun Zuo; Hui Ma; Ying Zhou; Ping Zhou; Liyong Wang; Miao Wang; Mahrukh Latif; Lu Kong

doi:10.1016/j.gendis.2020.12.010

Downregulation of nc886 contributes to prostate cancer cell invasion and TGFβ1-induced EMT

Genes Dis. 2021 Feb 9;9(4):1086-1098. doi: 10.1016/j.gendis.2020.12.010. eCollection 2022 Jul.

Authors

Ronghui Yang¹, Lingkun Zuo¹, Hui Ma¹, Ying Zhou¹, Ping Zhou², Liyong Wang¹, Miao Wang³, Mahrukh Latif⁴, Lu Kong¹

Affiliations

¹ Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, PR China.
² Biomedical Engineering Institute of Capital Medical University, Capital Medical University, Beijing 100069, PR China.
³ Department of Pathology, Beijing Friendship Hospital, The Second Clinical Medical College of Capital Medical University, Beijing 100050, PR China.
⁴ Department of Nuclear Medicine, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050010, PR China.

Abstract

Epithelial-to-mesenchymal transition (EMT) activation is important in cancer progression and metastasis. Evidence indicates that nc886 is a representative Pol III gene that processes microRNA products via Dicer and further downregulates its target gene transforming growth factor- β1 (TGF-β1), which is the most prominent inducer of EMT in prostate cancer (PC). Consistent with the previous literature, we found that nc886 downregulation was strongly associated with metastatic behavior and showed worse outcomes in PC patients. However, little is known about the association between nc886 and the EMT signaling pathway. We developed a PC cell model with stable overexpression of nc886 and found that nc886 changed cellular morphology and drove MET. The underlying mechanism may be related to its promotion of SNAIL protein degradation via ubiquitination, but not to its neighboring genes, TGFβ-induced protein (TGFBI) and SMAD5, which are Pol II-transcribed. TGF-β1 also override nc886 promotion of MET via transient suppression the transcription of nc886, promotion of TGFBI or increase in SMAD5 phosphorylation. Both nc886 inhibition and TGFBI activation occur regardless of their methylation status. The literature suggests that MYC inhibition by TGF-β1 is attributed to nc886 downregulation. We incidentally identified MYC-associated zinc finger protein (MAZ) as a suppressive transcription factor of TGFBI, which is controlled by TGF-β1. We elucidate a new mechanism of TGF-β1 differential control of Pol II and the transcription of its neighboring Pol III gene and identify a new EMT unit consisting of nc886 and its neighboring genes.

Keywords: EMT; MET; Non-coding RNA; Prostate cancer; TGF-β1.