Estrogen-Responsive Gene MAST4 Regulates Myeloma Bone Disease

Abstract

Our previous data showed that young female multiple myeloma (MM) patients had a low frequency of osteolytic lesions. Based on this clinical observation, we found that estrogen cell signaling played a regulatory role in MM bone disease (MMBD), and the estrogen‐responsive gene microtubule‐associated serine/threonine kinase family member 4 (MAST4) was a critical factor. The presence of estrogen in cell cultures promoted MAST4 expression in MM cells, while knocking down estrogen receptor 1 (ESR1) inhibited MAST4 expression. Chromatin immunoprecipitation assay suggested a binding site of ESR1 on the MAST4 promoter. Bisphosphonates, such as zoledronic acid (ZOL), which was widely used in MMBD control, could stimulate MAST4 expression in MM cells by promoting ESR1 expression. MAST4 interacted with phosphatase and tensin homolog (PTEN), therefore regulating the PI3K‐Akt‐mTOR pathway and the expression of downstream cytokines, such as CCL2/3/4. MAST4 knockdown (MAST4‐KD) or ESR1 knockdown (ESR1‐KD) MM cells had repressed PTEN activity, elevated PI3K‐Akt‐mTOR activity, and increased CCL2/3/4 expressions. Coculture of MAST4‐KD or ESR1‐KD MM cells with pre‐osteoclasts (pre‐OCs) stimulated OC formation in vitro, whereas neutralizing antibodies of CCL2/3/4 attenuated such stimulation. In mouse models, mice inoculated with MAST4‐KD or ESR1‐KD MM cells had severer MMBD than control knockdown (CTR‐KD). The correlations between MAST4 and ESR1 expressions in MMBD, as well as related cell signaling pathways, were confirmed in analyses using gene expression profiles (GEPs) of patients' MM cells. The negative correlation of MAST4 expression and occurrence of MMBD was further validated by patients' immunohistochemical tissue array. Overall, our data suggested that estrogen cell signaling negatively regulated MMBD through MAST4. © 2022 American Society for Bone and Mineral Research (ASBMR).

Microtubule-Associated Serine/Threonine (MAST) Kinases in Development and Disease

“…The search for estrogen response genes revealed, among others, MAST4. The study further showed that MAST4 is a negative regulator of MMBD and that the levels of MAST4 in MM cells negatively correlate with the severity of MMBD; high estrogen pathway activation levels correlated with high levels of MAST4 [30]. Pathway analyses suggested that MAST4 regulates the PI3-Kinase and mTOR pathways and that MAST4 colocalizes and co-immunoprecipitates with PTEN in MM cells.…”

“…Phosphorylation of the carboxy-terminal domain of PTEN reduces its activity and prevents PTEN from degradation, suggesting that MAST2 regulates PTEN activity and stability in vivo [29]. This MAST kinase-dependent inhibition of PTEN activity was also observed in multiple myeloma cell lines, where knockdown of MAST4 leads to reduced PTEN activity and increased activity of proteins involved in the mTOR signaling pathway [30]. The PTEN/MAST2 interaction might also play an important role in neuronal homeostasis.…”

“…MAST4 was identified as an estrogen response gene that was upregulated in female patients with multiple myeloma (MM) associated with low osteolytic lesions [69]. A recent investigation confirmed this association and revealed a mechanistic insight into the role of MAST4 in MM [30]. MM can be accompanied by characteristic lytic bone lesions derived from malignant plasma cells accumulating in the bone marrow, a syndrome called MM bone disease (MMBD).…”

Nuclear MAST4 Suppresses FOXO3 through Interaction with AKT3 and Induces Chemoresistance in Pancreatic Ductal Carcinoma

“…Estrogen signaling negatively regulates multiple myeloma-associated bone lesions through MAST4. The reason behind this is the regulation of the PI3-kinase and mTOR pathways by MAST4 [16]. Underexpression of MAST4 is associated with survival in breast cancer patients [17].…”

MAST4 promotes primary ciliary resorption through phosphorylation of Tctex-1

“…MAST4 is a large protein (∼265 kD); it comprises 2,434 amino acids and encompasses a DUF1908, a serine/threonine kinase, and a post-synaptic density-95/disks large/zonula occludens-1 (PDZ) domain. MAST4 has several reported functions in neuroprotection, spermatogenesis, the progression of multiple myeloma bone disease, and cell fate determination of mesenchymal stromal cells in bones and cartilages ( Gongol et al, 2017 ; Lee et al, 2021 ; Cui et al, 2022 ; Kim et al, 2022 ). In this study, we describe the ciliary localization of MAST4 and the physical and functional interactions between MAST4 and Tctex-1 in ciliary resorption.…”