Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis

Abstract

The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.

Potential dual functional roles of the Y‐linked RBMY in hepatocarcinogenesis

“…Most conserved MSY and their X homologs are expressed ubiquitously in a wide variety of tissues, while those of diverged MSY genes are primarily expressed in the testis, ie SRY , and/or germ cells, ie TSPY and RBMY , and are likely to play crucial roles in male sex determination/differentiation and spermatogenesis 15,23,70,73 . Ectopic expression of MSY genes in other somatic tissues/organs could contribute sex differences in normal development, differentiation and physiology, 67 and disease initiation, progression, and treatment responses in male‐biased manners 15,71 . Indeed, ectopic expression of testis‐specific genes, ie SRY , TSPY , and RBMY , have been observed in normal and diseased somatic cells/tissues, and have been postulated to exert male‐specific actions on the normal and/or diseased development 14‐16,38,74,75 …”

Loss of Chromosome Y and Its Potential Applications as Biomarker in Health and Forensic Sciences

“…X-homologous genes are in blue, Y-specific genes are in black. SRY and TSPY are in blue because of the existence of some similarity to SOX3 and TSPX sequences on the X chromosome [Skaletsky et al, 2003;Lau et al, 2019]. Underlined in different colours are 3 different classes of genes: green, X-degenerate genes; red, ampliconic genes; and purple, X-transposed genes.…”

“…For example, TSPY has functions in the renewal of spermatogonia. This gene is also speculated to be involved in meiotic cycle regulation and is even considered to be a proto-oncogene [Lau et al, 2011;Lau et al, 2019]. Another important Y-chromosomal gene is SRY, which was reported by Yuan et al [2001] to be able to interact with the androgen receptor and negatively regulate its activity.…”

Y chromosome in health and diseases

“…Accordingly, expression of these testis-specific MSY genes in somatic tissues could exert male-specific effects on the respectively affected organs/cells. We surmise that low-level/spatiotemporal expression of these MSY gene(s) during development/ physiology could produce normal differences between the sexes [5,42,43], and aberrant/high level expression could result in male biases in the pathogeneses of various human diseases [6,27,41]. In particular, TSPY and its X homologue TSPX (TSPYL2) evolved from the same ancestral gene but diverged structurally in their encoded proteins to process contrasting functions in cell cycle regulation and androgen receptor (AR) transactivation [44,45].…”

“…In particular, TSPY and its X homologue TSPX (TSPYL2) evolved from the same ancestral gene but diverged structurally in their encoded proteins to process contrasting functions in cell cycle regulation and androgen receptor (AR) transactivation [44,45]. They represent a pair of homologues on the sex chromosomes, which could oppose each other in various biological processes [41]. TSPY is specifically expressed in the testis (Additional file 1: Figure S1E) and could serve important functions in spermatogonia stem cell renewal and male meiosis [46].…”