Anshabo et al.

CDK9 in Cancer

Consequently, acetylated cyclin T1 binds the second bromodomain overwhelming amount of known cancer-causing mutations,
(BDII) of BRD4 and supports the recruitment and transcriptional most tumors are reliant on continuously activated gene
activity of P-TEFb (122). In contrast to normal cellular expression. Therefore, it does not come as a surprise that
transcription, the HIV1 TAT protein has evolved the ability to many studies have been conducted to highlight the link
recruit the non-acetylated cyclin T1 directly from the inhibitory between P-TEFb and most known types of cancer. Here, we
complex to activate HIV1 transcription (102). first focus comprehensively on blood cancers since the rationale
In addition to cyclin T1, CDK9 is also acetylated on two N- for the use of CDK9 inhibitors can be best supported with known
terminal lysine residues, namely Lys44 and Lys48, by p300 and genetic aberrations and gene mutations underlaying these
GCN5 (Figure 7B) (123, 124). While p300 and GCN5 acetylate diseases. We also highlight the potential role of P-TEFb in
both lysine residues, Lys44 is the preferred site for p300 while solid tumors using breast, prostate, and hepatocellular cancers
GCN5 mainly targets Lys48 (123, 124). Contrary findings have as examples. Table 1 provides a summary of the studies
been reported regarding the outcome of CDK9 acetylation on its providing links between P-TEFb and a range of other cancers
kinase and transcriptional activity (123, 124). On the one hand, as well as those discussed in more detail below.
Fu et al. reported that acetylation of CDK9 on Lys44 increases its
activity as the mutation of Lys44 to Arginine or overexpression Hematological Malignancies
of histone deacetylases (HDAC1 and 3, directed towards Lys44) P-TEFb in Leukemia
markedly impaired CDK9’s kinase and transcriptional activities P-TEFb plays a well-recognized role in the pathogenesis of many
(123). On the other hand, Sabo et al. showed that acetylation of hematological malignancies, such as leukemia. This is
CDK9 inhibits the binding of ATP to CDK9 and thus hinders its particularly true in leukemia harboring a chromosomal
kinase activity (124). Recently, the latter finding was supported translocationw mutation on chromosome 11q23 (176). This
by a study showing that by counteracting GCN5-mediated Lys48 loci encodes for a histone 3 lysine 4 methyltransferase protein,
acetylation with sirtuin7, a nicotinamide adenine dinucleotide called mixed-lineage leukemia (MLL) (177). MLL is ubiquitously
(NAD)-dependent deacetylase, there was an increased expressed in myeloid and lymphoid progenitor cells and
transcriptional activity of P-TEFb (125). increases the expression of a cluster of HOXA homeobox
genes (e.g. HOXA7 and 9) and the gene for the HOX-
Regulation by Ubiquitination dimerization partner, MEIS1 (177). These genes control self-
Polyubiquitination of CDK9 and its negative regulator HEXIM1 renewal of hematopoietic stem cells and are downregulated
provides an additional mechanism for the regulation of P-TEFb during hematopoietic differentiation (178). For reasons not
(Figures 7A, B) (29, 126). Recruitment of the SCF E3 ubiquitin clearly defined, chromosome 11 frequently undergoes an in-
ligase core components (S-phase kinase-associated protein 1 frame translocation mutation at the locus 11q23, where the 5’
(SKP1), cul-1, and p45SKP2) by cyclin T1 through its C-terminal end of MLL (containing its target gene binding motifs) is fused
PEST domain (residues 709-726) mediates polyubiquitination and with the 3’ end of a wide variety of unrelated partner genes,
subsequent degradation of CDK9 by proteasomes (29). Since the generating chimeric MLL fusion proteins (Figure 9) (179). These
protein level of CDK9 does not change in a manner akin to kinases fusion proteins are aberrant transcription factors that increase
regulating the cell cycle (59), the functional relevance of the expression of HOXA and MEIS1 genes, leading to a pre-
proteolytic degradation of CDK9 to its regulation is not clear. leukemic state by blocking hematopoietic differentiation (177).
Interestingly, contrary to the well-known function of The actively proliferating pre-leukemic progenitor cells are
ubiquitination, HIV1 transactivation by TAT is increased by the highly susceptible to secondary mutations (e.g., mutation in
ubiquitination of CDK9 which facilitates the formation of a the fms-like tyrosine kinase (FLT3) receptor) which aids in
ternary complex between P-TEFb, TAT, and TAR RNA (127). their transformation into acute leukemia (180).
TAT also recruits the UBE2O ubiquitin ligase in the cytoplasm to MLL rearrangement leukemia has a poor prognosis and
ubiquitinate HEXIM1 in a non-degradative manner (128). This accounts for approximately 10% of all cases of acute leukemia
ubiquitination step releases HEXIM1 from 7SK snRNP and in humans, irrespective of age. Specifically, MLL fusion is
liberates P-TEFb for transport from the cytoplasmic pool to the associated with > 70% of infantile acute lymphoblastic
nucleus (128). Similarly, ubiquitination of HEXIM1 by human leukemia (ALL), 35 – 50% of infant acute myeloid leukemia
double minute-2 protein (HDM2, Figure 7A), a p53-specific E3 (AML), and 1-15% of therapy-related leukemia (e.g. patients
ubiquitin ligase, does not lead to proteasome-mediated treated with topoisomerase II inhibitors) (177).
degradation, but instead increases its sequestering and thus MLL is involved in more than 100 different rearrangements
inhibition of P-TEFb, suggesting a role of ubiquitination beyond and 64 translocation partner genes have been identified
proteasome-mediated degradation (126). (Figure 9) (179). Despite a large number of partners, only nine
proteins account for more than 90% of MLL rearrangements,
namely AF4, AF9, ENL, AF6, AF10, ELL, AF1p, AF17, and
THE ROLE OF P-TEFB IN CANCER SEPT6 (179). The majority of these translocation partners
collectively associate to form a large macromolecule called
A plethora of genetic aberrations have been discovered as ENL-interacting proteins or elongation-assisting proteins
underlying causes for blood and solid cancers. Despite the (EAP) (181). EAP consist of three major components (1): SEC

Frontiers in Oncology | www.frontiersin.org 12 May 2021 | Volume 11 | Article 678559