Challenges and opportunities for the diverse substrates of SPOP E3 ubiquitin ligase in cancer

Abstract

The Speckle-type POZ protein (SPOP), a substrate adaptor of the cullin-RING E3 ligase complex, mediates both the degradation and non-degradative ubiquitination of substrates, which are crucial for regulating various biological functions and cellular processes. Dysregulation of SPOP-mediated ubiquitination has been implicated in several cancers. Emerging evidence suggests that SPOP functions as a double-edged sword: acting as a tumor suppressor in prostate cancer (PCa), hepatocellular carcinoma (HCC), and colorectal cancer (CRC), while potentially serving as an oncoprotein in kidney cancer (KC). Therefore, SPOP's role in tumorigenesis appears to be tissue- or context-dependent. Numerous downstream substrates of SPOP have been identified across various cancers, where they regulate carcinogenesis, metabolic reprogramming, cell death, immune evasion, therapy resistance, and tumor microenvironment (TME) remodeling. However, the definitive role of SPOP in these cancers requires further investigation. A comprehensive understanding of the molecular mechanisms of SPOP in different cancer types will provide new insights into its function in oncogenesis, potentially advancing anti-cancer drug development. Here, we summarize the latest findings on SPOP's functions and structural features, its regulatory mechanisms, the roles of its substrates in various cancers, and SPOP-targeting strategies.

Keywords: SPOP; cancer; diverse substrates; functions; therapeutic targeting.

Figure 1

Ubiquitination and degradation of target proteins. This figure illustrates the process of ubiquitination, where target proteins are tagged with ubiquitin molecules, signaling their degradation by the 26S proteasome. The process begins with the activation of ubiquitin by the E1 enzyme, followed by its transfer to the E2 conjugating enzyme. The E3 ligase then facilitates the attachment of ubiquitin to the target protein, often in the form of a polyubiquitin chain, which serves as a recognition signal for the proteasome. However, when a protein is tagged with a single ubiquitin (monoubiquitination), it may not lead to degradation but instead may regulate non-proteolytic functions, such as modifying protein activity or localization. Once the polyubiquitinated protein is recognized by the proteasome, it is unfolded and translocated into the proteolytic core for degradation. HECT, Homology to E6AP C-terminus; RBR, RING homology-in-between-RING; RING: Really interesting new gene.

Figure 2

The structure of CRL3. CRL3 is composed of cullin 3, RBX1, and a BTB protein, with SPOP serving as an example of a BTB protein in this complex. The interaction domains are shown: red indicates the interaction between RBX1 and cullin 3, while white represents the interaction between the BTB domain and cullin 3. BTB: Bric-à-brac/Tramtrack/Broad; CRL3: Cullin-RING ligase 3; RBX1: RING-box protein 1; SPOP: Speckle-type POZ protein.

Figure 3

Structural overview of SPOP. (A) The SPOP protein consists of five key domains: the N-terminal MATH domain, which binds substrates containing the SBC motif (a serine/threonine-rich peptide motif, Φ-π-S-S/T-S/T, where Φ is nonpolar and π is polar); an internal BTB/POZ domain, which interacts with Cullin 3 and facilitates SPOP dimerization; a BACK domain, which mediates secondary dimerization; and a C-terminal NLS. (B) The structure of SPOP, along with its hotspot mutations in prostate cancer, is shown. BTB: Bric-à-brac/Tramtrack/Broad; MATH: Meprin and TRAF homology; NLS: nuclear localization sequence; SBC: SPOP-binding consensus.

Figure 4

Regulatory functions of SPOP across multiple cancer types. This figure highlights the roles of SPOP in prostate cancer, breast and gynecologic cancers, digestive system malignancies, diffuse large B-cell lymphoma, choriocarcinoma, Ewing sarcoma, bladder cancer, and kidney cancer.

Figure 5

Functions of SPOP Substrates in PCa. This figure outlines the functional roles of SPOP substrates in PCa, highlighting how the ubiquitination-and either degradation or non-degradation-of specific substrates by SPOP impacts key cellular processes such as cell growth, apoptosis, androgen receptor signaling, and tumor progression. The diagram emphasizes how dysregulation of these processes, often resulting from SPOP mutations, contributes to the development and progression of PCa. PCa: prostate cancer; SPOP: Speckle-type POZ protein.

Figure 6

Functional roles of SPOP substrates in breast cancer and gynecologic cancer. The figure encapsulates the multifaceted roles of SPOP substrates in the oncogenic processes of breast cancer and gynecologic cancer. By regulating various pathways—ranging from growth factor signaling to immune evasion and hormonal regulation—SPOP substrates are pivotal in determining the aggressiveness and progression of these malignancies. SPOP: Speckle-type POZ protein.

Figure 7

Functional roles of SPOP substrates in digestive system tumors. This figure illustrates the diverse roles of SPOP substrates in the oncogenic processes of digestive system cancers. By regulating pathways such as immune evasion, SPOP substrates play a crucial role in the aggressiveness and progression of these tumors. SPOP: Speckle-type POZ protein.

Figure 8

Functional roles of SPOP substrates in other tumor types. This figure illustrates the diverse roles of SPOP substrates in various cancers, including lung cancer, DLBCL, choriocarcinoma, Ewing sarcoma, and bladder cancer. By regulating pathways such as signaling and immune evasion, SPOP substrates play a crucial role in the aggressiveness and progression of these tumors. DLBCL: diffuse large B-cell lymphoma; SPOP: Speckle-type POZ protein.

Figure 9

Potential oncogenic roles of SPOP in KC. The SPOP contributes to oncogenesis in KC by targeting multiple substrates. Specifically, the cytoplasmic accumulation of SPOP promotes the ubiquitination and degradation of Daxx, DUSP7, Gli2, and PTEN, enhancing cell proliferation and inhibiting apoptosis. Additionally, SPOP mediates the ubiquitination and degradation of SETD2, resulting in decreased H3K36me3, which may facilitate renal carcinogenesis. Furthermore, cytoplasmic SPOP prevents the degradation of the AR in the nucleus, leading to the activation of AR-driven pathways and the progression of KC. AR: androgen receptor; H3K36me: Trimethylation of histone H3 lysine 36; Kidney cancer: KC; SETD2: SET domain-containing 2; SPOP: Speckle-type POZ protein.