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Review
, 78 (19), 5481-5491

Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies

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Review

Low-Molecular-Weight Cyclin E in Human Cancer: Cellular Consequences and Opportunities for Targeted Therapies

Joseph A Caruso et al. Cancer Res.

Abstract

Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (CDK2), is central to the initiation of DNA replication at the G1/S checkpoint. Tight temporal control of cyclin E is essential to the coordination of cell-cycle processes and the maintenance of genome integrity. Overexpression of cyclin E in human tumors was first observed in the 1990s and led to the identification of oncogenic roles for deregulated cyclin E in experimental models. A decade later, low-molecular-weight cyclin E (LMW-E) isoforms were observed in aggressive tumor subtypes. Compared with full-length cyclin E, LMW-E hyperactivates CDK2 through increased complex stability and resistance to the endogenous inhibitors p21CIP1 and p27KIP1 LMW-E is predominantly generated by neutrophil elastase-mediated proteolytic cleavage, which eliminates the N-terminal cyclin E nuclear localization signal and promotes cyclin E's accumulation in the cytoplasm. Compared with full-length cyclin E, the aberrant localization and unique stereochemistry of LMW-E dramatically alters the substrate specificity and selectivity of CDK2, increasing tumorigenicity in experimental models. Cytoplasmic LMW-E, which can be assessed by IHC, is prognostic of poor survival and predicts resistance to standard therapies in patients with cancer. These patients may benefit from therapeutic modalities targeting the altered biochemistry of LMW-E or its associated vulnerabilities. Cancer Res; 78(19); 5481-91. ©2018 AACR.

Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to disclose.

Figures

Figure 1:
Figure 1:. The unique biochemical activities of LMW-E versus FL cyclin E and their consequences.
(A) (i) Cyclin E (FL 50 kDa) is an activating subunit of CDK2 that promotes kinase activity (small yellow star) during the G1-S-phase transition. Tumor-specific LMW-E isoforms are generated by (ii) alternative translation from methionine 46 (40 kDa) and (iii) NE-mediated cleavage of full-length cyclin E at two N-terminal sites (45/44 kDa and 35/33 kDa; doublets due to phosphorylation events) (66,105). LMW-E isoforms demonstrate higher binding affinity for CDK2, promoting hyperactivation of the kinase (large yellow star). (iv) In western blot analysis of normal (N) and tumor (T) tissue (using a C-terminally-directed antibody), LMW-E isoforms characteristically resolve as five distinct bands beneath FL cyclin E. In half of LMW-E-expressing breast tumors, cyclin E is also overexpressed; in the other half, however, LMW-E is expressed in the absence of full-length cyclin E (B). (i) When the pRb pathway is unaltered by oncogenic events, hypophosphorylated pRb binds to and sequesters E2F family transcription factors in G0-phase. (ii) FL cyclin E activates CDK2, leading to the hyperphosphorylation and inactivation of pRb, thereby releasing E2Fs to activate S-phase gene expression and progression. (iii) However, CDK inhibitors (e.g. p27) can inhibit the FL cyclin E-CDK2 complex (even if FL cyclin E is overexpressed) and prevent S-phase progression. (iv) Hyperactive LMW-E-CDK2 complexes can localize to the nucleus and hyperphosphorylate pRB; (v) even in the presence of CDK inhibitors, thereby promoting insensitivity to negative growth signals. (C) Hyperactive LMW-E-CDK2 complexes have other consequences. (i) FL Cyclin E-CDK2 can phosphorylate the substrate HBO-1; however, (ii) only constitutive hyperphosphorylation by LMW-E-CDK2 can promote HBO-1-dependant EMT and stemness properties, suggesting that cell cycle context-independent phosphorylation of HBO-1 alters its histone acetyltransferase activity in a pro-tumorigenic manner. (D) The proper timing of DNA replication and mitosis is essential to genome integrity. (i) One mechanism to ensure the fidelity of this process is feedback control through CDC25c, which promotes the proper timing of mitotic entry and exit through the activation of cyclin B-CDK1 and PLK1. (ii) Overexpression of FL cyclin E results in the improper phosphorylation of CDC25c and premature mitotic entry, but maintains the phosphorylation of CDC25c, delaying mitotic progression to cytokinesis and thereby largely preventing genomic instability. (iii) LMW-E overexpression also initiates premature mitotic entry; however unlike FL cyclin E, LMW-E cannot sustain CDC25c phosphorylation, resulting in faster mitotic exit and genomic instability. (iv) Genomic instability is further promoted by centrosome amplification induced by both FL cyclin E and LMW-E overexpression. (E) (i) FL cyclin E is largely restricted to the nucleus and therefore has limited opportunities to interact with cytoplasmic proteins. (ii) In contrast, LMW-E lacks an N-terminal nuclear localization signal promoting its accumulation in the cytoplasm where it can interact with novel binding partners including ACLY. LMW-E-CDK2 enhances ACLY activity (independent of phosphorylation), thereby promoting intracellular lipid accumulation and pro-tumorigenic phenotypes, including migration and invasion.
Figure 2:
Figure 2:. The prognostic significance of LMW-E.
Clinically, breast cancers are stratified into three groups, HR positive breast cancer, HER2 positive breast cancer, and TNBC based on the pathohistological assessment the of ER, PR, and HER2 expression. These breast tumor types are characterized by dramatic differences in clinical course and are treated using tailored therapeutic approaches. Immunohistochemical analysis of cyclin E or phosphorylated CDK2 and scoring according to the nuclear (FL)-to-cytoplasmic (LMW) cyclin E ratio identifies a patient population in each breast cancer subtype expressing high levels of LMW-E relative to FL cyclin E (approximately 50% of HR positive cancers, 75% of HER2 positive cancers, and 80% of TNBC). Within each of these subtypes, patients whose tumors express high LMW-E relative to FL-cyclin E have significantly worse survival outcomes than patients whose tumors predominantly express FL cyclin E. Data reviewed here suggest that LMW-E-expressing tumors are resistant to commonly used targeted therapeutics and may benefit from a combination of current therapeutic approaches with either anti-CDK2 based therapy or therapeutic strategies targeting specific vulnerabilities of LMW-E overexpressing tumors.

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