The Y-located proto-oncogene TSPY exacerbates and its X-homologue TSPX inhibits transactivation functions of androgen receptor and its constitutively active variants

Abstract

The gonadoblastoma gene, testis-specific protein Y-encoded (TSPY), on the Y chromosome and its X-homologue, TSPX, are cell cycle regulators and function as a proto-oncogene and a tumor suppressor respectively in human oncogenesis. TSPY and TSPX competitively bind to the androgen receptor (AR) and AR variants, such as AR-V7, at their conserved SET/NAP domain, and exacerbate and repress the transactivation of the AR/AR-V7 target genes in ligand dependent and independent manners respectively. The inhibitory domain has been mapped to the carboxyl acidic domain of TSPX, truncation of which renders TSPX to be stimulatory while its transposition to the C-terminus of TSPY results in an inhibitory hybrid protein. TSPY and TSPX co-localize with the endogenous AR, in the presence of ligand, on the promoters and differentially regulate the expression of the endogenous AR target genes in the androgen-responsive LNCaP prostate cancer cells. Transcriptome analysis shows that TSPY and TSPX expressions differentially affect significant numbers of canonical pathways, upstream regulators and cellular functions. Significantly, among the common ones, TSPY activates and TSPX inhibits numerous growth-related and oncogenic canonical pathways and cellular functions in the respective cell populations. Hence, TSPY and TSPX exert opposing effects on the transactivation functions of AR and AR-Vs important for various physiological and disease processes sensitive to male sex hormone actions, thereby not only affecting the pathogenesis of male-specific prostate cancer but also likely contributing to sex differences in the health and diseases of man.

Testis‐specific protein, Y‐linked 1 activates PI3K/AKT and RAS signaling pathways through suppressing IGFBP3 expression during tumor progression

“…The ectopic activation of TSPY1 is frequently observed in various somatic cancers, and some potential mechanisms associated with the involvement of TSPY1 in tumor progression have been reported . In the present study, we presented a novel mechanism underlying the promotion of TSPY1 on IGFBP3‐mediated tumor progression (Figure ).…”

“…The ectopic activation of TSPY1 is frequently observed in various somatic cancers, and some potential mechanisms associated with the involvement of TSPY1 in tumor progression have been reported. [15][16][17][18][19] In the present study, we presented a novel mechanism underlying the promotion of TSPY1 on IGFBP3-mediated tumor progression ( Figure 10). We identified that TSPY1 promoted the activation of both PI3K/AKT/mTOR/BCL2 and RAS/RAF/MEK/ERK/JUN F I G U R E 6 Knockdown of insulin growth factor binding protein 3 (IGFBP3) promotes the activation of PI3K/AKT and RAS pathways in A549 and HepG2 cells.…”

“…For example, TSPY1 potentiates cell proliferation and promotes a rapid transition from G 2 to M phase through binding to cyclin B1 and enhancing the kinase activity of cyclin B1/cyclin‐dependent kinase 1 complex . It increases protein synthesis and gene transcription through interacting with the eukaryotic translation elongation factor 1A, and exacerbates the transactivation of endogenous androgen receptor and activates a number of growth‐related and oncogenic canonical pathways . Recently, we reported that TSPY1 promotes cell proliferation through suppressing the ubiquitin‐specific peptidase 7‐mediated p53 function .…”

“…15,16 It increases protein synthesis and gene transcription through interacting with the eukaryotic translation elongation factor 1A, 17 and exacerbates the transactivation of endogenous androgen receptor and activates a number of growth-related and oncogenic canonical pathways. 18 Recently, we reported that TSPY1 promotes cell proliferation through suppressing the ubiquitin-specific peptidase 7-mediated p53 function. 19 All these accumulating findings improve our knowledge of the mechanism underlying TSPY1 functions under physiological or pathological conditions.…”

The Role of Number of Copies, Structure, Behavior and Copy Number Variations (CNV) of the Y Chromosome in Male Infertility

“…Nonetheless, the lack of known mutations of this gene alone in infertile men does not allow confirming what it does in human spermatogenesis. Testis-specific protein Y-linked (TSPY) is considered a proto-oncogene that antagonizes its X-linked homologue (TSPX) [142]. To date, the function of TSPY in the spermatogenesis is controversial [21]: Some authors hypothesize that it might act as a pro-proliferative factor in a dosage-dependent manner [143,144]; however, recently this view has been questioned [145] suggesting a possible population stratification bias [21].…”