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Role of the Aggresome Pathway in Cancer: Targeting Histone Deacetylase 6–Dependent Protein Degradation

¹ Division of Hematology-Oncology, Mattel Children's Hospital and ² Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; and ³ Division of Biology, California Institute of Technology, Pasadena, California

Requests for reprints: Kathleen M. Sakamoto, Division of Hematology-Oncology, Mattel Children's Hospital University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, CA 90095-1752. Phone: 310-794-7007; Fax: 310-206-8089; E-mail: kms{at}ucla.edu.

	Abstract

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 
Misfolded or aggregated proteins have two fates: they are either refolded with the help of chaperones or degraded by the proteasome. Cells also have an alternative pathway that involves intracellular "storage bins" for misfolded intracellular proteins known as aggresomes. Aggresomes recruit motor proteins that transport misfolded or aggregated proteins to chaperones and proteasomes for subsequent destruction. There is emerging evidence that inhibiting the aggresome pathway leads to accumulation of misfolded proteins and apoptosis in tumor cells through autophagy. We discuss the role of aggresomes in cancer and the potential to target this pathway for therapy. [Cancer Res 2008;68(8):2557–60]

	Protein (Mis)Folding and Aggregation

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 
Newly synthesized proteins must overcome several obstacles on their way to becoming functional molecules. Small proteins fold through a sequence of folding intermediates. During folding, partially folded proteins expose hydrophobic domains that lead to inappropriate associations and protein aggregation. Aggregation is toxic to cells and, due to high concentrations of macromolecules, causes a significant increase in the association constants of unfolded polypeptides over those in dilute solution. Effects of protein aggregation are amplified by the fact that stable folding of a domain cannot occur until the entire protein is synthesized. This is particularly important during synthesis of identical nascent polypeptides on polysomes, where numerous polypeptides expose the same aggregation-prone domains leading to increased risk of aggregation (1).

The ultimate fate of a protein is either correct folding or aggregation (1). Whether a polypeptide chain folds correctly or whether it aggregates is dependent on particular mutations, modification, mistakes during translation, or unequal synthesis of subunits (1). Misfolding can also be promoted by pH, temperature, ionic strength, and redox environment. Because a certain level of protein misfolding is inevitable, cells have adapted various quality control mechanisms to minimize misfolding and to eliminate misfolded proteins before aggregation (2, 3).

	Unfolded Protein Response Pathway

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 
Another important pathway in cells to regulate misfolded proteins is the unfolded protein response (UPR). Proteins synthesized in the endoplasmic reticulum (ER) are properly folded with the help of ER chaperones. Misfolded proteins are disposed of by ER-associated protein degradation (ERAD). When the level of misfolded proteins exceeds the folding capacity of the ER, cells activate a feedback mechanism known as the ER stress response (4). Expression of ER chaperones and ERAD-associated proteins is induced to decrease protein synthesis and, hence, the burden on the ER. There are four classes of agents that induce ER stress; they are inhibitors of glycosylation, calcium metabolism, reducing agents, and hypoxia. Finally, the ER stress response can result in activation of apoptosis (5).

Three transmembrane proteins regulate the mammalian ER stress response. PERK is a transmembrane kinase, ATF6 is a transmembrane transcription factor, and IRE1 is a transmembrane RNase. These three proteins maintain integration of the stress response and are critical for cell survival. ER stress-induced apoptotic pathways act through proapoptotic and antiapoptotic proteins, such as bcl-2, p53, and c-abl. Stress-activated protein kinase and c-Jun NH₂-terminal kinase (JNK) are also activated (5). Recently, the role of UPR in tumorigenesis has been investigated (6). As tumors increase in size, cells are exposed to several environmental stressors, including hypoxia, limited nutrients, and acidosis. Exposure to chemotherapy also activates UPR, resulting in sensitivity to DNA cross-linking agents (e.g., cisplatin); however, there is also evidence that activation of the stress response could confer resistance to drugs [e.g., topoisomerase II inhibitors (6)]. Clearly, the role of the ERAD and ER stress response is a complex issue due to the heterogeneity of tumor response.

	Chaperones and Ubiquitin-Proteasome System

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 
Molecular chaperones have evolved to assist with folding of newly synthesized proteins and refolding of proteins damaged by stress and cellular injury. Chaperones bind to and stabilized exposed hydrophobic residues through ATP-dependent interactions, allowing the protein to achieve proper folding (7). Chaperones do not seem to catalyze folding, but rather, they prevent intermolecular and intramolecular interactions between partially folded or misfolded polypeptides. This is an evolutionarily conserved mechanism from bacteria to eukaryotes to maintain proper folding after protein synthesis (1). Second, proteins that are unable to fold properly are targeted for degradation by the ubiquitin-proteasome system. The proteasome is a multisubunit complex found in the cytosol and nucleus that degrades cytosolic, nuclear, secretory, and transmembrane proteins into smaller peptides (8, 9). Misfolded secretory and transmembrane proteins are retained in the lumen or membrane of the ER and then retrotranslocated back to the cytosol and delivered to the proteasome (1). When correct folding is difficult or impossible and degradation is not performed rapidly, proteins interact with other unfolded or partially folded proteins, leading to the formation of aggregates (3). Cells then destroy protein aggregates through the aggresome pathway.

	The Aggresome Pathway

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 
Recent studies have shown a proteasome-independent pathway that eliminates misfolded polyubiquitinated proteins, known as the aggresome (Fig. 1 ; ref. 1). The initial aggregation process seems to occur cotranslationally, as nascent chains are coming off the polysome. If nascent peptides do not fold correctly, they will coaggregate to form a single aggresomal particle. In cells, these particles are uniform in size, supporting the idea that a fixed number of proteins aggregate to form a single particle (1). These particles are produced throughout the cytosol. After their formation, the aggresomal particles are transported toward the microtubule organizing center (MTOC), where they are sequestered into a single large cellular garbage bin-like structure known as the aggresome (1). Movement of the aggresome particle is an active process and requires intact microtubules and association with motor dynein. In cells treated with the microtubule-depolarizing agent nocodazole, the aggresome remains distributed throughout the cytosol. Furthermore, electron microscopy examination of aggresomes showed that these particles consist of multiple loosely associated particles.

View larger version (42K): [in this window] [in a new window] [Download PPT slide]   Figure 1. The aggresome pathway. Unfolded or misfolded proteins can originate from translating polysomes, from proteins retrotranslocated from the ER to the cytosol, or from proteins damaged by stress. If these unfolded/misfolded proteins fail to fold correctly and are not degraded by the proteasome, they can form aggregates throughout the cells. These aggregates are transported in a microtubule-dependent manner to the MTOC that requires the dynein/dynactin motor complex. HDAC6 acetylates -tubulin and associates with dynein to facilitate transport of aggregated bodies through the cytosol to lysosomes for degradation. HDAC6 coordinates the cell response to protein aggregate formation. Balance between HDAC6 and its partner p97/VCP determines the fate of polyubiquitinated misfolded proteins. The recruitment of HDAC6 to ubiquitinated proteins leads to the induction of a HSP90-dependent pathway that triggers protection against cell stress (1, 18).

	Recruitment of Aggresomes to the Degradation Machinery

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

Similar to chaperones, proteasomes interact with aggresomes. Proteasomes associate with aggresomes relatively late after small aggresomal particles are delivered to the MTOC. The pathways regulating interaction between aggresomes and chaperones or proteasomes have yet to be determined. Finally, clearance of aggregated proteins seems to activate autophagy. Autophagy is one of the primary pathways by which large structures, such as mitochondria and peroxisomes, are degraded in cells (1). Aggresomes are thought to be engulfed by autophagosomes, which then fuse to lysosomes, resulting in degradation of protein matter by lysosomal hydrolases.

Autophagy is activated by cellular stress, including those that trigger the aggresome pathway leading to degradation by lysosomes. There is recent evidence that the aggresome and autophagy pathways are linked. Studies on parkin-mediated K63-linked polyubiquitination seems to couple misfolded proteins to the dynein motor complex through interaction with histone deacetylase 6 (HDAC6), resulting in the formation of aggresomes and clearance by autophagy (11). Furthermore, studies on viruses have shown that viral replication and assembly often occur in inclusions that form at pericentriolar sites close to the MTOC or in specialized nuclear domains called ND10/PML bodies, similar to aggresomes (12). Protein degradation by basal constitutive autophagy is important to avoid accumulation of polyubiquitinated protein aggregates and development of diseases, such as Huntington's, Parkinson's, or Alzheimer's. The polyubiquitin-binding protein p62/SQSTM1 is degraded by lysosomes. Recent articles suggest that p62 is required for both the formation and the degradation of polyubiquitin-containing bodies by autophagy (13). It is likely, therefore, that autophagy and aggresome formation in cancer cells are linked and targeting both with inhibitors could be potentially synergistic.

Molecular studies to understand the aggresome pathway have implicated specific signaling molecules. One question is: how do cells recognize aggregated proteins and result in the formation of aggresomes? Published reports suggest that the sequestration of aggregated proteins into single aggresome is induced by cellular signaling mechanisms. Activation of the mitogen-activated protein kinase kinase (MEKK1) increases formation of aggresomes (14). MEKK1 seems to act at a relatively late stage of aggresome formation and affects sequestration of particles into pericentriolar aggresomes. The kinase activity of MEKK1 is required, suggesting that phosphorylation of downstream substrates is critical for aggresome formation. Previous studies showed that MEKK1-regulated pathways involve JNK, extracellular signal-regulated kinase, and p38. Interestingly, the effect of MEKK1 on aggresome formation does not seem to involve any of these kinases, suggesting that there are novel yet unidentified signaling pathways activated by cellular stress resulting from aggresomes.

	HDAC6 and the Aggresome Pathway

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 
HDAC6 is a member of the class II HDAC family and is known to deacetylate -tubulin and increase cell motility. HDAC6 is mainly localized in the cytoplasm and has two catalytic domains with deacetylase activity. The COOH-terminal domain is able to deacetylate -tubulin both in vitro and in vivo, and this activity is reversibly inhibited by trichostatin A (TSA; ref. 15). HDAC6 plays an essential role in aggresomal protein degradation because it can bind to both polyubiquitinated proteins and dynein proteins, thereby recruiting protein cargo to dynein motors to transport misfolded proteins to aggresomes (16). Previous work suggests that targeting both the proteasome-dependent pathways with bortezomib and the aggresome pathway in tumor cells could induce greater accumulation of polyubiquitinated proteins and significant cell stress followed by activation of apoptosis (17).

HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates (18). Studies by Boyault et al. (18) showed that HDAC6 senses ubiquitinated cellular aggregates and induces the expression of major cellular chaperones by triggering the dissociation of a repressive HDAC6/HSF1/HSP90 complex and subsequent HSF1 activation. The other known target of HDAC6 is HSP90 chaperone activity that adds to the multifunctionality of the protein and provides further rationale to target HDAC6 for cancer therapy (18). Therefore, HDAC6 seems to be a master regulator of the cell protective response to cytotoxic protein aggregate formation.

The cellular concentration of HDAC6 and its partner, p97/VCP, determines the outcome of polyubiquitinated misfolded proteins (Fig. 1). An excess of HDAC6 favors the accumulation of ubiquitinated, misfolded proteins, resulting in the formation of aggresomes. The abundance of p97/VCP results in the release of HDAC6 and delivery of ubiquitinated proteins to the proteasome for degradation. The accumulation of ubiquitinated proteins results in HDAC6-mediated transport along microtubules into aggresomes and final degradation by the lysosomes. In this manner, HDAC6 regulates the recruitment of the autophagic machinery to destroy the aggregates (1, 18).

	Role of HDAC6 in Cancer

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 
There is increasing evidence that HDAC6 plays a role in cancer cells and may be a target for drug development. HDAC6 is an estrogen-regulated gene that has prognostic significance in estrogen receptor (ER)-positive breast cancer cells (19). Overexpression of HDAC6 in MCF-7 breast cancer cells increased cell motility, suggesting a role for HDAC6 in metastases (19). One study showed that elevated HDAC6 protein expression by immunohistochemical staining in 139 consecutively archived human breast cancer tissues was associated with improved survival in patients who were ER positive and received tamoxifen (19). The combination of farnesyl transferase inhibitor lonafarnib and paclitaxel seems to enhance HDAC6-dependent tubulin deacetylation in both breast and small cell lung carcinoma cells (20). HDAC6 has additional functions in integrating signaling and cytoskeleton remodeling. Zhang et al. (21) showed that cortactin, which localizes to regions of cells undergoing active membrane remodeling, is a genuine substrate of HDAC6. Furthermore, cortactin has been found to be overexpressed in several carcinomas (22). Therefore, HDAC6 could be a viable target for cancer therapy.

	Tubacin Is an Inhibitor of HDAC6

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 
Recently, Stuart Schreiber's laboratory at Massachusetts Institute of Technology/Broad Institute isolated a small-molecule inhibitor of HDAC6 identified through a multidimensional chemical genetic screen of 7,392 small molecules and cell-based assay (23, 24). This inhibitor, known as tubacin, inhibits -tubulin deacetylation in mammalian cells. TSA is a broad HDAC inhibitor, whereas tubacin is specific for the tubulin deacetylase activity of HDAC6. These compounds inhibit the HDAC6 deacetylase activity by chelating a Zn²⁺ cation and may also alter the formation of complexes of HDAC6 with other intracellular proteins, such as HSP90, Dia2, and protein phosphatase-1 (15). Tubacin does not seem to affect global histone deacetylation, gene expression profiling, or cell cycle progression (23, 24). This drug binds to one of the catalytic domains of HDAC6 that contains the tubulin deacetylase activity. Recent data suggest that tubacin treatment does not affect microtubule stability but rather affects cell motility in lymphocytes (24). Recently, more selective inhibitors of HDAC6 have been identified (25). Several compounds were shown to act synergistically with paclitaxel in ER-positive breast cancer cells.

The effects of tubacin has been studied in normal and neoplastic cells (17). Overexpression of HDAC6 in primary lymphocytes and T-cell lines increases cell migration mediated by cytokines. Knockdown of HDAC6 in T cells decreases chemotactic mobility independent of its enzymatic activity (15). Treatment of multiple myeloma cells with tubacin resulted in decreased cell growth at an IC₅₀ of 2 to 5 µmol/L (17). No toxicity was observed in normal peripheral blood mononuclear cells. Tubacin treatment in combination with bortezomib resulted in increased -tubulin acetylation and accumulation of polyubiquitinated proteins in multiple myeloma cells (17). These cells undergo apoptosis through a caspase-8–dependent pathway. Tubacin was also found to inhibit interaction of HDAC6 with dynein and augmented activation of JNK, caspase-3, caspase-8, and caspase-9. Furthermore, treatment with the proteasome inhibitor bortezomib and tubacin together induced synergistic antitumor activity in multiple myeloma cells (17). Published data therefore provide rationale for combined therapy in clinical trials for patients with multiple myeloma.

	Conclusions

Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 
Recent studies on the aggresome pathway and inhibitors of HDAC6 suggest an emerging field in cancer therapy. Tubacin has been shown to act synergistically with other agents in multiple myeloma cells to increase cellular stress and induce apoptosis. We have found tubacin to be effective to inhibit growth of acute lymphoblastic leukemia cell lines as a single agent (data not shown). Further investigation is warranted to elucidate the signaling pathways that regulate HDAC6-induced apoptosis, mechanisms of tubacin action, and role of the aggresome pathway in other tumors.

	Acknowledgments

 
Grant support: Department of Defense grant W81XWH-06-1-0192 and MEC/Fulbright fellowship grant EX2005-0517 (A. Rodriguez-Gonzalez); NIH postdoctoral fellowship grants T32HL086345 (T. Lin) and T32CA9056 (A.K. Ikeda); American Academy of Pediatrics (T. Simms-Waldrip); and NIH grants HL75826 and HL83077, American Cancer Society grant RSG-99-081-01-LIB, Department of Defense grant CM050077, and Leukemia and Lymphoma Society Translational Research Grant 6019-07 (K.M. Sakamoto). K.M. Sakamoto is a Scholar of the Leukemia and Lymphoma Society.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/26/07. Revised 12/27/07. Accepted 1/ 2/08.

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Top Abstract Protein (Mis)Folding and... Unfolded Protein Response... Chaperones and Ubiquitin... The Aggresome Pathway Recruitment of Aggresomes to... HDAC6 and the Aggresome... Role of HDAC6 in... Tubacin Is an Inhibitor... Conclusions References

 

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This Article Abstract Full Text (PDF) Correction (v69,p4092) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rodriguez-Gonzalez, A. Articles by Sakamoto, K. M. Search for Related Content PubMed PubMed Citation Articles by Rodriguez-Gonzalez, A. Articles by Sakamoto, K. M. Related Collections Cellular Pathobiology: Metabolism and Physiology Therapeutics and Targets Therapeutics and Targets: Identification, Validation, and Markers