Abstract
Recent advancements in cancer research have shown that cancer stem cell (CSC) niche is a crucial factor modulating tumor progression and treatment outcomes. It sustains CSCs by orchestrated regulation of several cytokines, growth factors, and signaling pathways. Although the features defining adult stem cell niches are well-explored, the CSC niche is poorly characterized. Since membrane trafficking proteins have been shown to be essential for the localization of critical proteins supporting CSCs, we investigated the role of TUBB4B, a probable membrane trafficking protein that was found to be overexpressed in the membranes of stem cell enriched cultures, in sustaining CSCs in oral cancer. Here, we show that the knockdown of TUBB4B downregulates the expression of pluripotency markers, depletes ALDH1A1+ population, decreases in vitro sphere formation, and diminishes the tumor initiation potential in vivo. As TUBB4B is not known to have any role in transcriptional regulation nor cell signaling, we suspected that its membrane trafficking function plays a role in constituting a CSC niche. The pattern of its expression in tissue sections, forming a gradient in and around the CSCs, reinforced the notion. Later, we explored its possible cooperation with a signaling protein, Ephrin-B1, the abrogation of which reduces the self-renewal of oral cancer stem cells. Expression and survival analyses based on the TCGA dataset of head and neck squamous cell carcinoma (HNSCC) samples indicated that the functional cooperation of TUBB4 and EFNB1 results in a poor prognosis. We also show that TUBB4B and Ephrin-B1 cohabit in the CSC niche. Moreover, depletion of TUBB4B downregulates the membrane expression of Ephrin-B1 and reduces the CSC population. Our results imply that the dynamics of TUBB4B is decisive for the surface localization of proteins, like Ephrin-B1, that sustain CSCs by their concerted signaling.
Highlights
Cancer stem cells (CSCs) are a minority population of cells in a tumor microenvironment, analogous to normal adult stem cells, which can self-renew and differentiate into the different clones in bulk tumor tissue [1, 2]
Tubulin and bIII tubulin are reported in cancer [24, 38]. bII tubulin is shown to regulate Voltage-Dependent Anion Channels (VDACs) in the mitochondrial outer membrane, which act as a critical regulator of the Warburg effect observed in cancer cells [39, 40]
Even though the expression of TUBB4B was evaluated in some studies, its role in the regulation of oral cancer CSCs is not well explored in oral cancer
Summary
Cancer stem cells (CSCs) are a minority population of cells in a tumor microenvironment, analogous to normal adult stem cells, which can self-renew and differentiate into the different clones in bulk tumor tissue [1, 2]. They have been reported to be decisive in the initiation, propagation, multilineage differentiation, relapse, and drug resistance in various cancers [3, 4]. Further analysis has shown that a synchronized activation of both WNT and BMP gradients fine-tune the process [9, 10] Another class of proteins that regulate intestinal crypt stem cell fate is the one involved in Eph/Ephrin signaling. WNT-mediated generation of a reverse gradient of Eph receptors and Ephrin-B1 has shown to be critical in maintaining the balance of self-renewal and differentiation in intestinal crypts [11]. We provide evidence of TUBB4B-mediated regulation of Ephrin-B1 localization that supports the CSC niche in oral cancer
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