An EMT–primary cilium–GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis

Abstract

The epithelial-mesenchymal transition (EMT) and primary ciliogenesis induce stem cell properties in basal mammary stem cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon entry into intermediate EMT states by activating ciliogenesis inducers, including FGFR1. The resulting primary cilia promote ubiquitination and inactivation of a transcriptional repressor, GLIS2, which localizes to the ciliary base. We show that GLIS2 inactivation promotes MaSC stemness, and GLIS2 is required for normal mammary gland development. Moreover, GLIS2 inactivation is required to induce the proliferative and tumorigenic capacities of the mammary tumorinitiating cells (MaTICs) of claudin-low breast cancers. Claudin-low breast tumors can be segregated from other breast tumor subtypes based on a GLIS2-dependent gene expression signature. Collectively, our findings establish molecular mechanisms by which EMT programs induce ciliogenesis to control MaSC and MaTIC stemness, mammary gland development, and claudin-low breast cancer formation.

GLIS1-3: Links to Primary Cilium, Reprogramming, Stem Cell Renewal, and Disease

“…However, GLIS2 does not contain a consensus CLS sequence suggesting that its ciliary localization might be mediated by a different mechanism. Regulation of GLIS2 transcriptional activity by primary cilium-associated mechanisms is discussed below in more detail [ 11 , 44 ].…”

“…The transcriptional activation by GLIS1-3 is mediated by the recruitment of co-activators, such as EP300/p300, to the transactivation domain (TAD) at their carboxy-terminus ( Figure 1 ). Although GLIS2 can activate gene transcription, in several cell types it appears to function largely as a repressor [ 3 , 5 , 8 , 10 , 11 , 12 , 13 ]. GLIS2 repressor function is, in part, mediated through its recruitment of the co-repressor, C-terminal binding protein 1 (CTBP1) [ 5 , 14 ].…”

“…Deficiency in GLIS2 causes nephronophthisis, a cystic renal disease that is the most common cause of end-stage renal disease in young adults [ 8 , 12 , 26 , 27 ], while GLIS1 was found to play a critical role in the regulation of intraocular pressure by maintaining normal trabecular meshwork functions [ 28 ]. GLIS1-3 have also been implicated in several malignancies, including breast and colorectal cancer, and leukemia [ 11 , 16 , 29 , 30 , 31 , 32 , 33 , 34 ]. A translocation involving CBFA2/RUNX1 Partner Transcriptional Co-Repressor 3 ( CBFA2T3 , also referred to as ETO2 ) and GLIS2 has been implicated in acute mega-karyoblastic leukemia, while GLIS1-Paired Box 8 (PAX8) and GLIS3-PAX8 translocations are associated with hyalinizing trabecular tumors, a rare thyroid neoplasm stemming from thyroid follicular cells [ 13 , 16 , 33 , 35 , 36 , 37 , 38 ].…”

“…Dysregulation of these processes are causally involved in many diseases. Recent studies have demonstrated that GLIS proteins can regulate stem cell renewal, reprogramming, EMT, and cell lineage determination and that in certain cases this involves the primary cilium [ 11 , 13 , 40 , 41 , 42 , 43 , 44 ]. In this review, we focus particularly on several recent studies that identified roles for GLIS1-3 and circGLIS RNAs in the regulation of stem cell renewal, EMT, differentiation, and reprogramming, and their relevance to several diseases, including cancer.…”

Anhydroicaritin Inhibits EMT in Breast Cancer by Enhancing GPX1 Expression: A Research Based on Sequencing Technologies and Bioinformatics Analysis

“…Glutathione peroxidase 1 (GPX1) is a vital antioxidant enzyme that can catabolize the hydrogen oxide entering the human body and reduce peroxide's damage to the body (Huang et al, 2018). As one of the important cell biology processes, epithelial-mesenchymal transition (EMT) plays a key role in multiple links of tumor metastasis (Wilson et al, 2021;Yang et al, 2021). A previous study also revealed that GPX1 inhibits EMT progression in cancer and plays an anticancer role (Meng et al, 2018).…”