PRRX1 induced by BMP signaling decreases tumorigenesis by epigenetically regulating glioma‐initiating cell properties via DNA methyltransferase 3A

Abstract

Glioma-initiating cells (GICs), a major source of glioblastoma recurrence, are characterized by the expression of neural stem cell markers and the ability to grow by forming non-adherent spheres under serum-free conditions. Bone morphogenetic proteins (BMPs), members of the transforming growth factor- family, induce differentiation of GICs and suppress their tumorigenicity.However, the mechanisms underlying the BMP-induced loss of GIC stemness have not been fully elucidated. Here, we show that paired related homeobox 1 (PRRX1) induced by BMPs decreases the CD133-positive GIC population and inhibits tumorigenic activity of GICs in vivo. Of the two splice isoforms of PRRX1, the longer isoform, pmx-1b, but not the shorter isoform, pmx-1a, induces GIC differentiation. Upon BMP stimulation, pmx-1b interacts with the DNA methyltransferase DNMT3A and induces promoter methylation of the PROM1 gene encoding CD133. Silencing DNMT3A maintains PROM1 expression and increases the CD133-positive GIC population. Thus, pmx-1b promotes loss of stem-cell-like properties of GICs through region-specific epigenetic regulation of CD133 expression by recruiting DNMT3A, which is associated with decreased tumorigenicity of GICs.

Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years

“…BMPs regulate expression of various target genes in glioma-initiating cells. In this figure, the roles of PRRX1 ( Tanabe et al, 2022 ) and gremlin1 ( Yan et al, 2014 ) are shown. Of the two splice isoforms of PRRX1, only pmx-1b induces differentiation of glioma-initiating cells.…”

“…We found that the expression of paired related homeobox 1 (PRRX1) is induced by BMPs in glioma-initiating cells. The longer isoform of PRRX1, pmx-1b, interacts with DNA methyltransferase 3A (DNMT3A) and induces promoter methylation of the PROM1 gene encoding CD133, thereby attenuating stem cell-like properties ( Tanabe et al, 2022 ) ( Figure 3 ). We have also reported that the tyrosine kinase Eph receptor A6 (EPHA6) promotes apoptosis in BMP-2-sensitive glioma-initiating cells ( Raja et al, 2019 ).…”

“…BMPs induce the expression of gremlin1, an antagonist of BMP, which is involved in the maintenance of pro-tumorigenic functions and stem cell properties of glioma-initiating cells. Modified from Tanabe et al (2022) .…”

Promising Advances in LINC01116 Related to Cancer

“…Brain gliomas are the most common primary malignant tumors in the central nervous system, presenting with an increasing mortality rate. Several patients present with an OS time of less than 2 years ( Mondal and Kulshreshtha, 2021 ; Petridis et al, 2021 ; Tanabe et al, 2021 ; Tu et al, 2021 ). Wang et al (2020c) found that the upregulation of LINC01116 in glioma cells is related to poor prognosis.…”

Functional Roles of CD133: More than Stemness Associated Factor Regulated by the Microenvironment

“…Whereas both isoforms of this protein can bind to the PROM1 promoter, only the long isoform (PRRX1A) with OAR (otp, aristaless, and rax) domain in its C-terminal region (PRRX1A) interacts with DNMT3A and induces PROM1 promoter P1 methylation. Both PRRX1A and DNMT3A silencing increase CD133 + positive subpopulation even in the presence of BMP-4 and enhance their tumorigenic capacity [ 54 ].…”