HDAC6 inhibition suppresses chondrosarcoma by restoring the expression of primary cilia

Abstract

Chondrosarcoma is a bone tumor characterized by the secretion of a cartilage-like extracellular matrix. It has been proved to lack extracellular sensor primary cilia. This study aimed to illustrate a feasible therapeutic method for chondrosarcoma by regulating primary cilia assembly through inhibiting histone deacetylases 6 (HDAC6) activation. In order to detect the interaction between primary cilia and HDAC6 in human chondrosarcoma, Tubastatin A and small interfering RNA (siRNA) were used to inhibit the endogenous expression of HDAC6. Cell viability test and Transwell assay were applied to evaluate the effects of malignant biological properties. Primary cilia staining and related proteins were detected. The abnormal expression of HDAC6 and cilia intraflagellar transport protein 88 (IFT88) was found in chondrosarcoma tissues. The inhibition of HDAC6 could downregulate the proliferation of chondrosarcoma cells in a concentration- and time-dependent manner and suppress the invasion capacity of tumor cells. Besides, the downregulation of HDAC6 exhibited a negative effect on the proliferation of relevant proteins but a positive effect on the primary cilia-related expression of IFT88 and acetylated α-tubulin. Primary cilia restoration could be observed after HDAC6 siRNA transfection. The Aurora A-HDAC6 cascade was involved in regulating primary cilia resorption by affecting α-tubulin deacetylation and Tubastatin A could inhibit chondrosarcoma cell growth in vivo. These results indicate that restricting HDAC6 can restore primary cilia assembly accompanied with suppressed chondrosarcoma cell proliferation and invasion capacities. Thus, promoting primary cilia restoration by targeting HDAC6 may be a feasible potential therapeutic method for chondro-sarcoma treatment.

Primary Cilium in Cancer Hallmarks

“…AURKA is the point of convergence between these two pathways, and cilium disassembly occurs downstream of its activation. AURKA was found to be upregulated in non-ciliated ovarian and clear cell renal cell carcinoma cancer cells [44,45], and HDAC6 inhibition restored primary cilia in chondrosarcoma and cholangiocarcinoma cancer cells, suppressing cell proliferation and their invasion capacity [53,54]. Similarly, HEF1 overexpression was associated with the metastasis of breast cancer and melanoma [55,56].…”

Chondrosarcoma: A Rare Misfortune in Aging Human Cartilage? The Role of Stem and Progenitor Cells in Proliferation, Malignant Degeneration and Therapeutic Resistance

“…Human chondrosarcoma cells lose primary cilia with increasing malignity [ 132 ], which may be either a consequence of rapid proliferation or the prerequisite for enhanced cell cycle progression. Recently, histone deacetylase 6 (HDAC6) has been implicated in suppression of cilia formation in human chondrosarcoma [ 133 ]. Notably, osteochondroma have a random cilia orientation compared to normal growth plate chondrocytes where cilia are arranged parallel to the growth axis, which assures the correct assembly of chondrocytes in stacked columns [ 134 ].…”

A synthetic combinatorial approach to disabling deviant Hedgehog signaling

“…Whereas HDAC1 inhibition has been shown to directly affect GLI acetylation 20 , genetically based elimination or chemical inhibition of HDAC6 with selective small molecules is sufficient to block a subset of GLI transcriptional targets and SMO-M2-driven medulloblastoma growth in vivo 33 . In addition, HDAC6 inhibitors modulate primary cilium stability, an organelle that facilitates the relinquishing of SUFU suppression 2 , 34 and proteolytic processing of GLI3 into a transcriptional repressor 35 – 39 . Thus, IHR-SAHA could impact GLI activity directly by targeting HDAC1 and indirectly by altering aspects of primary cilium function.…”