Human germ/stem cell-specific gene TEX19 influences cancer cell proliferation and cancer prognosis

Abstract

BackgroundCancer/testis (CT) genes have expression normally restricted to the testis, but become activated during oncogenesis, so they have excellent potential as cancer-specific biomarkers. Evidence is starting to emerge to indicate that they also provide function(s) in the oncogenic programme. Human TEX19 is a recently identified CT gene, but a functional role for TEX19 in cancer has not yet been defined.MethodssiRNA was used to deplete TEX19 levels in various cancer cell lines. This was extended using shRNA to deplete TEX19 in vivo. Western blotting, fluorescence activated cell sorting and immunofluorescence were used to study the effect of TEX19 depletion in cancer cells and to localize TEX19 in normal testis and cancer cells/tissues. RT-qPCR and RNA sequencing were employed to determine the changes to the transcriptome of cancer cells depleted for TEX19 and Kaplan-Meier plots were generated to explore the relationship between TEX19 expression and prognosis for a range of cancer types.ResultsDepletion of TEX19 levels in a range of cancer cell lines in vitro and in vivo restricts cellular proliferation/self-renewal/reduces tumour volume, indicating TEX19 is required for cancer cell proliferative/self-renewal potential. Analysis of cells depleted for TEX19 indicates they enter a quiescent-like state and have subtle defects in S-phase progression. TEX19 is present in both the nucleus and cytoplasm in both cancerous cells and normal testis. In cancer cells, localization switches in a context-dependent fashion. Transcriptome analysis of TEX19 depleted cells reveals altered transcript levels of a number of cancer-/proliferation-associated genes, suggesting that TEX19 could control oncogenic proliferation via a transcript/transcription regulation pathway. Finally, overall survival analysis of high verses low TEX19 expressing tumours indicates that TEX19 expression is linked to prognostic outcomes in different tumour types.ConclusionsTEX19 is required to drive cell proliferation in a range of cancer cell types, possibly mediated via an oncogenic transcript regulation mechanism. TEX19 expression is linked to a poor prognosis for some cancers and collectively these findings indicate that not only can TEX19 expression serve as a novel cancer biomarker, but may also offer a cancer-specific therapeutic target with broad spectrum potential.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0653-4) contains supplementary material, which is available to authorized users.

Meiosis-like Functions in Oncogenesis: A New View of Cancer

“…Recent work in mice has demonstrated that the mammalian-specific gene Tex19.1 is required to promote normal levels of these meiotic recombination-initiating events (49). The human ortholog, TEX19, normally has expression restricted to the testis and embryo stem cells, but is also widely activated in cancer cells (31); importantly, this expression is required in a number of distinct cancer cell types to mediate proliferation and cancer stem-like cell self-renewal (50). While the mechanism of action of TEX19 in cancer cells remains unknown, this work further demonstrates the functional requirements for diverse meiotic chromosomal modulators, including regulators of meiotic recombination initiation, in oncogenesis.…”

Tex19.1 inhibits the N-end rule pathway and maintains acetylated SMC3 cohesin and sister chromatid cohesion in oocytes

“…Although the Tex19.1 −/− phenotype indicates that Tex19.1 plays a role in maintaining arm cohesion in oocytes, the biochemical function of TEX19.1 is poorly understood. Both mouse Tex19.1 and human TEX19 are functional in some nonmeiotic somatic cell types that naturally express these genes ( Reichmann et al, 2013 ; Tarabay et al, 2013 ; Planells-Palop et al, 2017 ). Therefore, to investigate whether the ability of mouse Tex19.1 to regulate sister chromatid cohesion is conserved in human TEX19 and extends from meiosis to mitosis, we expressed human TEX19 in human HEK293T cells that do not normally express this gene ( Fig.…”

“…Tex19.1 is a member of the mammal-specific family of TEX19 genes that duplicated during rodent evolution ( Kuntz et al, 2008 ). Mouse Tex19.1 is syntenic with human TEX19 , and these genes appear to have similar expression patterns in pluripotent cells and in fetal and postnatal male and female germ cells ( Öllinger et al, 2008 ; Kuntz et al, 2008 ; Hackett et al, 2012 ; Planells-Palop et al, 2017 ). Tex19.2 is expressed in somatic cells in the testis and at more restricted stages of gametogenesis ( Kuntz et al, 2008 ; Celebi et al, 2012 ; Hackett et al, 2012 ).…”

Meiotic gene activation in somatic and germ cell tumours

“…Recently, another CT gene involved in SPO11‐mediated recombination regulation in mammals, TEX19 , has been reported to be required for maintaining the proliferative state of cancer cells (Planells‐Palop et al ., ). The functional nature of human TEX19 in cancer cells remains unknown, but the TEX19 gene appears to be extensively activated in a range of cancer type (Feichtinger et al ., ; Zhong et al ., ).…”

“…Murine Tex19.1 appears to regulate a number of germ line biological functions, most likely via a defined association with the murine Ubr2 E3 ubiquitin ligase, and these include regulation of LINE1 transposition and the initiation of SPO11 meiotic recombination (Yang et al ., ; Reichmann et al ., ; Tarabay et al ., ; Crichton et al ., , ; MacLennan et al ., ). TEX19 is mammalian‐specific and so the D. melanogaster l(3)mbt tumour studies do not shed any light on whether TEX19 is required early in the oncogenic programme, as well as being required to maintain the proliferative status of cancer cells, although preliminary analysis of human tumour progression arrays suggests that it is activated early in the oncogenic programme (Planells‐Palop et al ., ).…”