Suppression of cancer stemness by upregulating Ligand-of-Numb protein X1 in colorectal carcinoma

Abstract

Cancer stem-like cells (CSCs) have been reported to play major roles in tumorigenesis, tumor relapse, and metastasis after therapy against colorectal carcinoma (CRC). Therefore, identification of colorectal CSC regulators could provide promising targets for CRC. Ligand-of-Numb protein X1 (LNX1) is one E3 ubiquitin ligase which mediates the ubiquitination and degradation of Numb. Although several studies indicate LNX1 could be a potential suppressor of cancer diseases, the functions of LNX1 in mediating cancer stemness remain poorly understood. In this study, LNX1 was identified as a negative regulator of cancer stemness in CRC, which was downregulated in colonospheres or side population (SP) cells. Furthermore, the coxsackievirus and adenovirus receptor (CXADR) was found to be one critical downstream mediator of cancer stemness regulated by LNX1. Interestingly, the anti-breast cancer drug tamoxifen was found to be an agonist of LNX1 and suppress cancer stemness in CRC. In sum, this study provided the evidences that LNX1 signaling plays important roles in regulating the stemness of colon cancer cells.

LNX1/LNX2 proteins: functions in neuronal signalling and beyond

“…A more recent study has now also implicated LNX1 in CRC [35]. Here the authors observed that LNX1 mRNA and protein were down-regulated in a population of putative cancer stem cells (side population cells) isolated from the CRC cell line HT29.…”

“…The most comprehensive studies linking LNX1/2 proteins to tumorigenesis are in relation to CRC [34,35]. The human LNX2 gene maps to chromosome 13q12.2-a region that is frequently amplified in CRC.…”

“…Detection of endogenous LNX1/2 proteins by Western blotting generally requires immunoprecipitation from tissue lysates [ 13 , 20 , 29–33 ], though LNX2 can be detected directly in brain lysates from mice at embryonic and early postnatal but not adult stages [ 13 , 28 ]. Both LNX1 and LNX2 can be detected directly by Western blotting in colorectal cancer (CRC) cell lines [ 34 , 35 ] but their detection in other cell lines has not been widely reported. Immunostaining for endogenous LNX1 protein has been reported in the perisynaptic Schwann cells of neuromuscular junctions [ 33 ], while LNX2 protein was detected broadly in most organs of embryonic day 16.5 mice [ 30 ].…”

The Molecular and Pathophysiological Functions of Members of the LNX/PDZRN E3 Ubiquitin Ligase Family

“…While the progression of colorectal carcinoma can be regulated by both LNX1 and LNX2, they act in opposing manners. While elevated levels of LNX2 were shown to promote the oncogenic potential of colorectal carcinoma through the maintenance of NOTCH and WNT signaling, both of which are required for cancer cell proliferation [ 87 ], LNX1 was observed to negatively regulate cancer stemness in colorectal carcinoma cells, in which LNX1 expression and CAR expression were inversely correlated, and CXADR (CAR-encoding gene) expression was shown to be inhibited upon treatment with tamoxifen, a drug frequently used in breast cancer chemotherapy [ 88 ] that stimulates LNX1 expression in the presence of estrogen receptor [ 89 ]. Contrary to expectation, Camps et al in 2013 [ 87 ] showed that LNX2 depletion reduced the levels of both NUMB and NOTCH1 proteins without affecting the levels of NUMB transcripts in SW470 (colorectal cancer cell line) cells, which was counterintuitive, considering that Lnx2 in zebrafish is commonly known to target Numb degradation [ 21 ].…”

LNX1 Contributes to Cell Cycle Progression and Cisplatin Resistance

“…In glioblastoma, LNX1 regulates Notch1 signaling and induces expansion of the glioma stem cell population [10]. Furthermore, several studies associated with cancer and LNX1 have suggested its role as a tumor regulator in various cancers, including gliomas and colorectal carcinoma [11,12]. LNX1 related protein, LNX2 is also reported to upregulate Wnt/beta-catenin pathway in colorectal cancers [13].…”