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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Cancer Ther. Author manuscript; available in PMC Sep 14, 2009.
Published in final edited form as:
Cancer Ther. Sep 1, 2009; 7(A): 219–226.
PMCID: PMC2743178
NIHMSID: NIHMS115742

PML: An emerging tumor suppressor and a target with therapeutic potential

Summary

Though originally discovered as a tumor suppressor in Acute Promyelocytic Leukemia (APL), the importance of promyelocytic leukemia protein (PML) in cancers of other origins has not been widely studied. Recent studies have shown that multiple types of cancers show decreased expression of PML protein, though the mechanisms leading to this down-regulation are unknown. Decreased expression of PML can result in loss of cell cycle control and prevention of apoptosis and is likely a key event in the promotion of oncogenesis. Many of these effects are due to changes in the transcriptional profile of the cell as a result of decreased size and number of PML nuclear bodies. Several mouse studies confirm the contribution of PML to oncogenesis and cancer progression. It is important to not only further define a role for PML as a tumor suppressor, but also to begin to develop strategies to target PML therapeutically.

Keywords: Cancer, pathways by PML, therapy

I. Introduction

Simply, cancer arises when normal cells grow out of control. There are numerous events that can lead to oncogenesis, ultimately involving activation of oncogenes, repression of tumor suppressor genes or both. Oncogenes often control cell division and differentiation. In cancer, oncogenes are expressed at times when they would not normally be present, leading to increased cell division and resistance to cell death. Conversely, tumor suppressor genes normally act to slow down cell division, repair DNA mistakes, and induce apoptosis. When these genes are mutated, leading to their inactivation, the gene product is either decreased or not functional, allowing the cell to divide uncontrollably and often leading to the development of cancer. In general, the protein product of a tumor suppressor gene is known as a tumor suppressor. While there are numerous tumor suppressors, some are more commonly inactivated than others. Notable tumor suppressors include Rb (retinoblastoma) which is involved in cell cycle regulation, p53 which is involved in DNA damage repair and apoptosis, and Pten which is anti-apoptotic. For those tumor suppressors involved in a wide variety of cancers, it is worthwhile to develop treatments that can target their activities. Therefore, it is also important to identify other tumor suppressors that play a large role in many different cases of oncogenesis. This review focuses on the activities of the tumor suppressor PML and suggests that PML is one such tumor suppressor worth targeting in cancer therapy.

PML was originally identified due to its involvement in a chromosomal translocation that causes the development of APL (de The et al, 1991). Since its discovery, studies have found that PML plays a role in many cellular processes including apoptosis, viral infection, transcriptional regulation, cell cycle regulation and DNA damage repair (Maul et al, 2000; Borden, 2002; Ching et al, 2005). The role of the PML translocation in APL provided the first indication that PML could act as a tumor suppressor and recent work has established this role for non-translocated PML. It has become clear that PML plays an extensive role in tumor suppression by promoting apoptosis and inhibiting cell growth through multiple mechanisms.

II. PML and PML NBs

PML is a member of the RBCC/TRIM family of proteins due to its N-terminal RING/B box/coiled-coil (RBCC) domain (Jensen et al, 2001). This domain is important for protein-protein interactions and is required for many of the activities of PML. The PML transcript undergoes extensive processing and alternative splicing resulting in more than 11 different isoforms, that primarily vary at the C-terminus of the protein (Jensen et al, 2001). These isoforms carry out both redundant and non-redundant functions in the cell which complicates many of the cellular studies of this protein. Furthermore, while most isoforms include a nuclear localization sequence and are found in the nucleus, some isoforms exist in the cytoplasm and at least one isoform, PML1, can shuttle between the two subcellular compartments. Interestingly, the nuclear forms of PML are known to reside in subnuclear structures that are known as PML nuclear bodies (PML NB) (also known as ND10 and PODs). Research has shown that PML NBs are responsible for many PML functions. Furthermore, PML NBs are disrupted in APL (de The et al, 1991; Kakizuka et al, 1991; Dyck et al, 1994) and reform when APL cells are treated with drugs known to induce remission in APL patients.

PML NBs have been proposed to act as cellular organizing centers for the coordinated regulation of different processes (Bernardi and Pandolfi, 2007). PML NBs range in size and number due to cell type, cell environment, and extracellular stimuli. More than 50 proteins are known to localize in PML NBs either constitutively or transiently. This varying composition is responsible for their involvement in so many cellular functions (Zhong et al, 2000; Buschbeck et al, 2007). For example, several proteins shuttle in and out of NBs in response to DNA damage including p53, ATR, MRE11, NBS1 and BLM (Dellaire and Bazett-Jones, 2004). In another case, proteins involved in the apoptotic pathways which localize in the NBs in response to cell-death signals include p53, Mdm2, Daxx, Bax, and p27Kip1 as well as many others (Hofmann and Will, 2003; Takahashi et al, 2004). The importance for PML in these subnuclear structures is highlighted by their absence in PML−/− primary cells, which can be recovered with the expression of exogenous PML (Zhong et al, 2000; Lallemand-Breitenbach et al, 2001). As a result, it is thought that PML is essential for the formation and stability of PML NBs.

PML NBs are associated with the nuclear matrix and at their periphery make contacts with chromatin fibers (Eskiw et al, 2004). These points of contact have been shown to be non-random in nature. The regions of the nucleus in which PML NBs are located are enriched in transcriptionally active genes; however, PML NBs have not been found to contain DNA themselves (Wang et al, 2004). The size, number, and position of PML NBs are not static, but change under normal and stress-induced conditions. Fluorescence recovery after photobleaching (FRAP) experiments have shown that the PML in PML NBs exchanges between the nucleoplasm and PML NBs as well as between different PML NBs (Wiesmeijer et al, 2002). Furthermore, other proteins move in and out of the nuclear bodies in response to environmental stimuli. For example, many DNA repair and checkpoint proteins localize to PML NBs in response to UV damage (Dellaire and Bazett-Jones, 2004). As such, aberrant expression of PML may have profound effects on these cellular processes.

III. Regulation of PML in cancer

Traditionally, the silencing of tumor suppressor genes is thought to follow Knudson’s two-hit hypothesis, meaning that two genetic mutations are required in the tumor suppressor gene, one in each allele. This is indeed the case for many cancer genes. However, recently, much work has described a new class of tumor suppressor genes that do not necessarily follow this classical definition (Paige, 2003). In fact, there are instances of haploinsufficient genes that only require mutation in one allele. Furthermore, epigenetic silencing has become important for many tumor suppressor genes, often due to hypermethylation of the tumor suppressor promoter (Paige, 2003). PML appears to belong, to the latest class of tumor suppressors, with regulation occurring mostly post-translationally, making it a unique model in the growing list of tumor suppressor proteins.

In addition to its disruption due to translocation in APL, loss of PML has been observed in many different types of cancer. An immunohistochemical analysis of tissue samples from tumors of several origins indicates that PML protein expression is abolished or greatly diminished in tumor cell lines derived from prostate adenocarcinomas, colon adenocarcinomas, breast carcinomas, lung carcinomas, lymphomas, CNS tumors (including medulloblastomas and oligodendroglial tumors), germ cell tumors, and non-Hodgkin’s lymphomas (Figure 1). Interestingly, there is no change in PML transcript levels in these tissues compared to their normal counterparts as assayed by in situ hybridization (Gurrieri et al, 2004). Furthermore, other studies have shown decreased PML in breast carcinomas, gastric cancer, small cell lung carcinomas, and invasive epithelial tumors (Koken et al, 1995; Gambacorta et al, 1996; Zhang et al, 2000; Lee et al, 2007). Lastly, in a few of these cancers, such as breast, prostate, and CNS tumors, loss of PML correlates with increased tumor grade (Gurrieri et al, 2004). These studies all highlight an important role for PML in tumor suppression; however, the mechanisms underlying the loss of PML are largely unknown. Despite this, there are examples of changes in PML in response to various stimuli, which may provide a hint as to the pathways by which PML expression is decreased in cancer cells. Furthermore, recent work in our laboratory has highlighted an important mechanism by which PML levels are controlled in the absence of extracellular stimuli. PML is known to be regulated by several distinct mechanisms. At the transcriptional level, PML gene expression can be up-regulated in response to a number of transducers and activators of transcription (STATs) and other interferon-stimulated transcription factors to bind to the PML promoter and stimulate PML mRNA transcription (Lavau et al, 1995; Stadler et al, 1995; Grotzinger et al, 1996; Heuser et al, 1998; Vannucchi et al, 2000; Dror et al, 2007; Kim et al, 2007). This can also be achieved through DNA damaging agents that promote p53 binding to the PML promoter (de Stanchina et al, 2004). Tumor necrosis factor α treatment can also up-regulate PML mRNA expression through a currently uncharacterized mechanism that involves histone deacetlyase 7 (HDAC7) (Gao et al, 2008). As mentioned previously, at the mRNA level, PML is subject to alternative splicing which directly controls which PML isoforms exist under certain conditions or in different cell types (Jensen et al, 2001). Several isoforms have restricted subcellular localizations, cytoplasmic or nuclear. Post-translationally, the functions of PML are controlled through the localization of PML as well as through multiple post-translational modifications. Cytoplasmic PML is capable of binding to nuclear isoforms of PML and sequestering the nuclear isoforms in the cytoplasm, thus controlling NB size and number (Bellodi et al, 2006a,b). Conversely, in response to TGFβ signaling, cytoplasmic isoforms of PML can be transported and maintained in the nucleus, thereby disrupting interactions of nuclear isoforms of PML with downstream players of TGFβ signaling such as Smads 2/3 and SARA (Lin et al, 2004).

Figure 1
Incidence of Decreased PML in Cancer

In the context of post-translational modifications, PML can be phosphorylated, sumoylated, acetylated, ubiquitinylated, and ISGylated (Kamitani et al, 1998; Duprez et al, 1999; Bernardi et al, 2004; Hayakawa and Privalsky, 2004; Scaglioni et al, 2006; Hayakawa et al, 2008; Lallemand-Breitenbach et al, 2008; Shah et al, 2008; Tatham et al, 2008; Weisshaar et al, 2008). All of these modifications control different aspects of PML function, either through changes in protein-protein interactions, localization, or stability. For example, sumoylation has been found to be integral for NB formation and is important for many of the contacts that PML makes with other proteins in the NB (Shen et al, 2006). In many instances sumoylation is coordinately controlled with phosphorylation of PML, leading to changes in PML function in response to many different signaling pathways. As mentioned previously, many of these modifications occur in response to specific extracellular stimuli, such as arsenic trioxide, which can promote phosphorylation of PML in an Erk2-dependent manner and which is required for the subsequent sumoylation of PML and its eventual degradation (Hayakawa and Privalsky, 2004).

In order to understand how PML is down-regulated in tumors of multiple origins, it is important to understand the regulation of PML in the absence of extracellular stimuli. Our lab has shown that PML stability can be controlled through interactions with the peptidyl-prolyl cis-trans isomerase Pin1. Since Pin1 causes a change in the two-dimensional and ultimately three-dimensional structure of the proteins with which it associates, Pin1 can have dramatic effects on target protein stability. This is indeed the case for the interaction between PML and Pin1. The ability of PML to interact with Pin1 controls the steady-state levels of PML in the cell. Interestingly, this interaction is dependent on site-specific phosphorylation of PML and is blocked by PML sumoylation (Reineke et al, 2008). Furthermore, Pin1 expression has been found to be elevated in many different cancers (Wulf et al, 2003). Thus, this pathway could contribute to the decreased levels of PML protein observed in many tumors and is consistent with decreases in PML protein accumulation without parallel changes in mRNA accumulation. Due to the various stimuli that can control post-translational modifications of PML, this pathway may be utilized under several different circumstances to down regulate PML protein levels in cancer. In another study, we showed that PML protein and NB levels are up-regulated through the interaction of PML with HDAC7, which may present another mechanism by which PML accumulation can be altered in cancer (Gao et al, 2008). The events regulating PML in response to these interactions with Pin1 and HDAC7 still need to be investigated fully. Interestingly, other studies have shown that PML can be stabilized by proteosome inhibitors and undergoes ubitquitin-dependent degradation (Cao et al, 2008; Lallemand-Breitenbach et al, 2008; Scaglioni et al, 2008; Tatham et al, 2008; Weisshaar et al, 2008), which could likely play a role in Pin1 and HDAC7 control of PML.

Perhaps the strongest evidence for the direct control of PML protein levels by another protein that is over-expressed during oncogenesis is the effects of casein kinase 2 (CK2) on PML. CK2 marks PML for ubiquitin-mediated degradation through site-directed phosphorylation. Importantly, in non-small cell lung carcinoma (NSCLC), PML is often decreased while CK2 is over-expressed. To link the regulation of PML by CK2 to these PML expression changes, NCSLC cell lines and primary human NSCLC specimens were examined for PML protein levels and CK2 activity. As expected, there was a direct correlation between decreased PML protein and enhanced CK2 activity (Scaglioni et al, 2006, 2008). These data strongly implicates this pathway in the loss of PML during NCSLC. It remains to be determined if this also occurs in other types of cancer where CK2 is elevated, such as in mammary tumors and lymphomas. Taken together, these data suggest that there may be multiple important pathways for regulating PML protein levels, thus highlighting the importance of modulating PML protein levels and activity in oncogenesis. It is also likely that other oncogenic pathways target PML to promote tumor formation.

IV. Control of cancer-inducing pathways by PML

As previously mentioned, PML and PML NBs are involved in a wide range of cellular processes. Interestingly, PML is able to act as a tumor suppressor through multiple mechanisms, controlling proteins involved in both the regulation of the cell cycle as well as apoptosis. This includes preventing cell cycle progression through interactions such as that with Rb and supporting apoptosis through NB proteins such as p53 and Daxx (Pearson and Pelicci, 2001; Takahashi et al, 2004). Thus, the down-regulation of PML can allow uncontrolled cell growth and oncogenesis. In general, in comparison to a normal cell, a cancer cell is characterized by uncontrolled growth accompanied by decreased cell death. Various studies indicate that PML is intimately involved in both of these processes. We have previously shown that a reduction of PML protein levels by siRNA leads to an increase in the proliferation of breast cancer cells. This can be modulated through the previously described interaction between PML and Pin1 (Reineke et al, 2008). Therefore, it is likely that agents known to induce Pin1 expression or activity will lead to decreased PML expression. One such class of agents is growth factors, which activate several pathways, at least one of which results in increased Pin1 (You et al, 2002), and thus likely decreased PML. While growth factors are required for normal cellular functions, many are over-expressed or their receptors show increased activity in cancer. Uncontrolled growth factor signaling eliminates the ability of PML to prevent too much cell growth, as it would in a normal cell. Interestingly, androgen has been shown to decrease protein levels of PML and therefore may utilize this pathway in some prostate cancers (Yang et al, 2004). In another study, it was shown that induction of PML is important for inhibition of cell growth in U87MG astrocyte cancer cells (Kim et al, 2007). Finally, several studies have indicated that overexpression of PML resulted in a decrease in the proliferation of several cancer cell lines which correlated with G1 arrest (Chan et al, 1997; Le et al, 1998; Son et al, 2005; Li et al, 2006).

The ability of PML to block cell proliferation is intertwined with its ability to stimulate cell death. PML has been shown to be involved in both extrinsic and intrinsic cell death pathways and therefore acts downstream of a wide range of death-inducing stimuli (Bernardi et al, 2008). We have shown that PML expression sensitizes MDA-MB-231 breast cancer cells to hydrogen peroxide-induced cell death (Reineke et al, 2008). In other cases, PML promotes DNA damage-induced apoptosis (Bernardi et al, 2008). As mentioned previously, there is a significant change in NB protein composition in response to extracellular stimuli, including that of DNA-damaging agents which promote movement of p53 and caspase-2 to NBs (Tang et al, 2005; Bernardi et al, 2008). By concentrating in the NB, many of the proteins involved in the same cellular response, are brought into close proximity of each other, thus promoting an efficient response through protein-protein interactions and protein modifications.

Recruitment of transcription factors to the NBs is particularly important. PML can affect transcription factor activity through direct interaction or the control of post-translational modification and stability of transcription factors. These changes by PML can be stimulatory or inhibitory to transcriptional activity of each transcription factor. Furthermore, PML targets transcription factors from both tumor suppressor and oncogenic pathways. PML binding to p53 is important in controlling its tumor suppressive functions (Bernardi et al, 2008). PML is able to control the transcriptional competence of p53 through modulation of its acetylation by p300 and site-specific phosphorylation by HIPK2 (Ferbeyre et al, 2000; Pearson et al, 2000; Moller et al, 2003). Furthermore, PML can control the stability of p53 via several distinct mechanisms, including PML binding to Mdm2 to prevent the latter’s interaction and subsequent ubiquitination of p53 or by promoting de-ubiquitination of p53 by the ubiquitin protease HAUSP (Everett et al, 1997; Li et al, 2002; Bernardi et al, 2004). PML can also abrogate the interaction between Mdm2 and p53 through promotion of phosphorylation of p53 by CK1 and Chk2 (Louria-Hayon et al, 2003; Alsheich-Bartok et al, 2008).

One family of transcription factors that has been shown to have both tumor-suppressive and oncogenic activity affected by PML is AP-1. c-Jun co-localizes with PML NBs in response to UV irradiation and the absence of PML interferes with the stimulation of the transcriptional activity of c-Jun by UV (Salomoni et al, 2005). Furthermore, PML can be immunoprecipitated in an AP-1 complex and has been shown to control the transcriptional activity of another AP-1 member, c-Fos, which has also been suggested to play a role in the tumor suppressive activity of PML (Vallian et al, 1998).

Other transcription factors implicated in oncogenesis that are known to associate with PML include NF-kappB and Myc. PML can bind to and sequester the RelA/p65 subunit of NF-κB in the NB, thereby preventing its binding to target promoters (Wu et al, 2003; Kuwayama et al, 2008). In turn, this prevents NF-κB from stimulating cell growth through the up-regulation of pro-survival genes such as survivin (LaCasse et al, 1998). Similarly, the transcriptional program of Myc has been shown to be altered in the absence of PML, though the mechanism of these changes is not well characterized (Cairo et al, 2005).

In this manner, many of the contacts made within the NB are integral to the tumor suppressive functions of PML (Figure 2). Changes in the abundance of PML can cause changes in a wide variety of cellular genes through the sequestration or modification of transcription factors in the NB. These are lost in instances where PML is downregulated or NBs are disrupted, such as in APL.

Figure 2
Loss of PML is an important step in tumorigenesis. Top panel

V. Evidence for a role of PML in cancer in vivo

While PML protein levels are down-regulated in human tumors, and several pathways are implicated in playing a role in this regulation, evidence to link these events together through mouse models is not very abundant. There are, however, a few studies to support the idea of PML as a tumor suppressor in vivo and perhaps a regulator in oncogenesis.

PML−/− mice develop normally, but are more prone to develop tumors induced by chemical insults than their wild type counterparts (Wang et al, 1998). Furthermore, the PML null animals are no longer protected by the ability of retinoic acid to inhibit tumor growth. Some of these effects are likely due to the loss of PML control of apoptotic pathways since the mice are unaffected by ionizing radiation and anti-Fas antibodies, two cell death-inducing treatments (Bernardi et al, 2008). Similarly, when PML −/− MEFs are integrated into nude mice, the mice grow larger fibrosarcomas and have increased tumor vascularization as compared to their wild type counterparts (Bernardi et al, 2006). These results provide evidence for a link between oncogenic pathways and PML.

When PML −/− mice are crossed with Pten +/− mice, the resulting animals have increased polyp number and size in the colon, thus further suggesting a role of PML in tumor suppression (Trotman et al, 2006). This work also supports cross-talk between the Pten and PML pathways. PML has been shown to control Pten nuclear localization and its activity (Song et al, 2008). Furthermore, when PML −/− mice are crossed with a transgenic mutant model of K-RasG12D-induced non-small cell lung cancer, the mice show increased tumor burden coupled with an increased malignant phenotype (Scaglioni et al, 2006). These data support the idea that the loss of PML observed in lung tumors is an important step in lung cancer progression. Similarly, a cross of PML−/− mice with a mouse model for leukemia expressing a human capethespin G promoter driven-PML-RARα APL translocation transgene, leads to increased tumor incidence and accelerated leukemia progression as compared to mice with PML (Rego et al, 2001). Finally, there is a previously characterized pathway whereby Ras induction of p53 is PML-dependent and required for Ras-induced senescence, another process linked to cancer incidence (Ferbeyre et al, 2000; Pearson et al, 2000). In contrast, there are examples where the loss of PML does not increase tumorigenesis. A cross of PML−/− mice with the breast cancer model MMTV/neu transgenic mice had no effect (Rego et al, 2001). However, in the majority of cases, loss of PML plays an integral role in controlling the speed and magnitude of cancer progression.

In comparison, overexpression of PML prevents cancer progression in a mouse model of skin carcinogenesis. Transgenic mice overexpressing PML in the epidermis and hair follicles showed decreased DMBA-induced papilloma number and size, as well as decreased progression from papilloma to carcinoma (Virador et al, 2008). Similarly, adenovirus-mediated over expression of PML in prostate cancer cell lines is able to prevent tumor growth when injected into nude-mice. Injection of adenovirus expressing PML into already established prostate-cancer cells did not prevent tumors in nude mice but decreased their growth by 64% (He et al, 1997). Overall, these in vivo studies suggest that targeting PML is a common target in oncogenesis and not just a side effect of the modulation of other proteins. Therefore we believe that PML warrants further investigation in carcinogenesis and may be an attractive target for therapeutics.

VI. Controlling PML in therapy

The literature contains many examples suggesting the importance of controlling PML activity and protein levels in oncogenesis. Many studies have aimed at determining how PML protein levels are down-regulated and the pathways by which PML is controlled. It is now time to begin to think about applying this information to the clinical setting. Future research will hopefully determine the cellular PML E3 ligases that may be pharmacologically targeted, or a specific modification of PML that stabilizes the protein under multiple conditions that may be manipulated. In the meantime, we can use the information available regarding the regulation of PML to re-induce its expression in tumors. Many currently used treatments for cancer already target PML expression. However, each by itself may not be effective to achieve high enough levels of PML. Therefore, by using combinations of already existing strategies that target PML expression, it may be possible to induce PML expression to endogenous levels. Combining drugs all aimed at manipulating PML may also allow using lower doses of each drug, hopefully leading to decreased side effects and increased efficacy. The existing cancer mouse models in which PML has been shown to effect cancer growth and progression provide a platform by which to test combinatorial treatments. For example, interferons, tumor necrosis factor alpha, DNA-damaging agents, apoptosis-inducing agents, and proteosome inhibitors are all agents that have been shown in cell culture to be able to up-regulate PML protein levels. It will be important to first validate the effects of these agents on PML in mouse models. Studies in this direction will perhaps lead to the development of new combinations of drugs that may not have previously been evident. There are many new cancer therapy targets and PML should be one of these targets. The work done by many since its discovery in APL clearly suggest that it plays a larger role in oncogenesis than originally expected.

Acknowledgments

We thank Dr. Samols for his comments on the manuscript. Hung-Ying Kao is supported by NIH (DK078965), the Pardee Foundation, and the American Cancer Society.

Abbreviations

APL
Acute Promyelocytic Leukemia
CK2
casein kinase 2
FRAP
Fluorescence recovery after photobleaching
HDAC7
histone deacetlyase 7
NSCLC
non-small cell lung carcinoma
PML NB
PML nuclear bodies
PML
promyelocytic leukemia protein
RB
retinoblastoma
RBCC
RING/B box/coiled-coil
STATs
signal transducers and activators of transcription

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