MBTPS2 acts as a regulator of lipogenesis and cholesterol synthesis through SREBP signalling in prostate cancer

Abstract

Background Prostate cancer is the most common cancer in men in the developed world, with most deaths caused by advanced and metastatic disease which has no curative options. Here, we identified Mbtps2 alteration to be associated with metastatic disease in an unbiased in vivo screen and demonstrated its regulation of fatty acid and cholesterol metabolism. Methods The Sleeping Beauty transposon system was used to randomly alter gene expression in the PtenNull murine prostate. MBTPS2 was knocked down by siRNA in LNCaP, DU145 and PC3 cell lines, which were then phenotypically investigated. RNA-Seq was performed on LNCaP cells lacking MBTPS2, and pathways validated by qPCR. Cholesterol metabolism was investigated by Filipin III staining. Results Mbtps2 was identified in our transposon-mediated in vivo screen to be associated with metastatic prostate cancer. Silencing of MBTPS2 expression in LNCaP, DU145 and PC3 human prostate cancer cells reduced proliferation and colony forming growth in vitro. Knockdown of MBTPS2 expression in LNCaP cells impaired cholesterol synthesis and uptake along with reduced expression of key regulators of fatty acid synthesis, namely FASN and ACACA. Conclusion MBTPS2 is implicated in progressive prostate cancer and may mechanistically involve its effects on fatty acid and cholesterol metabolism.

Integrated multi-omic analysis and experiment reveals the role of endoplasmic reticulum stress in lung adenocarcinoma

“…EIF2AK3 has been identified as an immune-related prognostic gene in breast cancer, exerting a role in tumor cell apoptosis and facilitating sustained protective antitumor immunity [ 28 ]. MBTPS2, a membrane-embedded zinc metalloprotease, activates signaling proteins involved in transcriptional control of sterol and the ER stress response [ 29 ], thus promoting the progression of prostate cancer [ 30 ] and colorectal cancer [ 30 ]. The RHBDD2 (Rhomboid domain containing 2) gene is found to be overexpressed in advanced stages of colorectal cancer (CRC) and potentially modulates the UPR pathway, thereby favoring cell migration, adhesion, and proliferation [ 31 ].…”

Combined Inhibition of UBE2C and PLK1 Reduce Cell Proliferation and Arrest Cell Cycle by Affecting ACLY in Pan-Cancer

“…Folding factors assist newly synthesized proteins in acquiring the correct three-dimensional fold, and a complex quality control system guarantees that only correctly folded proteins exit the ER. When misfolded proteins accumulate, the UPR is induced and ATF6 is activated after subsequent cleavage by S1P and S2P [76,77]. The activated ATF6 is released from the Golgi membrane and, upon transport into the nucleus, induces the expression of ER stress gene products [76,78].…”

“…Some studies have provided evidence that the decreases in S2P expression, and the absence of mature SREBP1 and ATF6 production, resulting in the failure to activate the UPR, can induce apoptosis in liposarcoma and prostate cancer cells [79,80]. A more recent study has found that the knockdown of MBTPS2 expression in human prostate cancer cells impaired cholesterol synthesis and uptake and reduced the expression of key regulators of fatty acid synthesis, FASN and ACACA, through SREBP signaling [77]. These data suggest that tumors driven in different key regulatory components of DNL and the UPR might respond dramatically to MBTPS2 inhibition.…”

Loss of ARID1A accelerates prostate tumourigenesis with a proliferative collagen-poor phenotype through co-operation with AP1 subunit cFos

“…RT-PCR was performed as described previously (3).Briefly, first-strand cDNA was produced by reverse transcription from extracted RNA samples using the High-Capacity cDNA Transcription kit (Applied Biosystems) following the manufacturers protocol. RTPCR was carried out using TaqMan Universal Master Mix (Thermo Fisher Scientific) with primer appropriate Universal ProbeLibrary probes (Roche).…”

“…Premature deaths from PC are a result of metastatic and/or recurrent disease for which there are no curative options. Building on our recent research on an in vivo Sleeping Beauty (SB) transposon based forward-mutagenesis screen (2,3), we explore putative role of ARID1A as a mechanism for progressive PC.…”