PMEPA1 Gene Isoforms: A Potential Biomarker and Therapeutic Target in Prostate Cancer

Abstract

The identification of prostate transmembrane protein androgen induced 1 (PMEPA1), an androgen responsive gene, came initially from the studies of androgen regulatory gene networks in prostate cancer. It was soon followed by the documentation of the expression and functional analysis of transmembrane prostate androgen-induced protein (TMEPAI)/PMEPA1 in other solid tumors including renal, colon, breast, lung, and ovarian cancers. Further elucidation of PMEPA1 gene expression and sequence analysis revealed the presence of five isoforms with distinct extracellular domains (isoforms a, b, c, d, and e). Notably, the predicted amino acid sequences of PMEPA1 isoforms show differences at the N-termini, a conserved membrane spanning and cytoplasmic domains. PMEPA1 serves as an essential regulator of multiple signaling pathways including androgen and TGF-β signaling in solid tumors. Structure-function studies indicate that specific motifs present in the cytoplasmic domain (PY, SIM, SH3, and WW binding domains) are utilized to mediate isoform-specific functions through interactions with other proteins. The understanding of the “division of labor” paradigm exhibited by PMEPA1 isoforms further expands our knowledge of gene’s multiple functions in tumorigenesis. In this review, we aim to summarize the most recent advances in understanding of PMEPA1 isoform-specific functions and their associations with prostate cancer progression, highlighting the potentials as biomarker and therapeutic target in prostate cancer.

Transcriptomic Analysis of LNCaP Tumor Xenograft to Elucidate the Components and Mechanisms Contributed by Tumor Environment as Targets for Dietary Prostate Cancer Prevention Studies

“…Of note, PMEPA1, a gene upregulated 3.7-fold, was identified as regulated by AR. Expression of this gene is induced by androgens and transforming growth factor beta [ 49 ], and the encoded protein suppresses the androgen receptor and transforming growth factor beta signaling pathways through interactions with Smad proteins [ 49 ]. Overexpression of this gene may play a role in multiple types of cancer [ 49 ].…”

“…Expression of this gene is induced by androgens and transforming growth factor beta [ 49 ], and the encoded protein suppresses the androgen receptor and transforming growth factor beta signaling pathways through interactions with Smad proteins [ 49 ]. Overexpression of this gene may play a role in multiple types of cancer [ 49 ]. This gene is also involved in downregulation of the androgen receptor (AR), enhancing ubiquitination and proteasome-mediated degradation of AR [ 49 ].…”

“…Overexpression of this gene may play a role in multiple types of cancer [ 49 ]. This gene is also involved in downregulation of the androgen receptor (AR), enhancing ubiquitination and proteasome-mediated degradation of AR [ 49 ]. Consistently, TGFb1 was also identified as top upstream regulator and causal network with an effect on AR ( Supplementary Materials 4 and 5 ).…”

PMEPA1 interference activates PTEN/PI3K/AKT, thereby inhibiting the proliferation, invasion and migration of pancreatic cancer cells and enhancing the sensitivity to gemcitabine and cisplatin

“…PMEPA1 is a tumor‐associated gene that has been found to be overexpressed exclusively in tumor tissues rather than nontumor diseases (Koido et al, 2016). Sharad et al described PMEPA1 as a potential biomarker for the progression of prostate cancer (Sharad, Dobi, et al, 2020). Zhang et al demonstrated that PMEPA1 promotes the EMT of colorectal cancer by activating BMP/TGF‐β signaling pathway (Zhang et al, 2019).…”

Prostate transmembrane androgen inducible protein 1 (PMEPA1): regulation and clinical implications

“…Studies have reported that PMEPA1-a inhibits the TGF-β signaling pathway through various steps ( 33 ). Additionally, TGF-β exerts regulatory control on PMEPA1 by modulating the ratio of Smad proteins and the converse is also true.…”