Biomarker: CDK9

Histology type: endometrial carcinoma

Country: China

Region: Changsha

Followed up time :

Subgroup 1 name : Low(CDK9 staining score ≤2)

Subgroup 1 number: 19

Subgroup 2 name: high(CDK9 staining score ≥3)

Subgroup 2 number: `3

Conclusion: In conclusion, our results provide evidence that CDK9 may be a potential prognostic biomarker and a promising therapeutic target for the treatment of endometrial cancer in the future.

Sample type : tissue

Sample method: immunohistochemistry

Expression pattern : high CDK9 ( staining ≥3+)

Expression elevation: The expression of CDK9 was divided into five levels: i) 1+, <10% positive cells; ii) 2+, 10–25% positive cells; iii) 3+, 26–50% positive cells; iv) 4+, 51–75% positive cells; v) 5+, >75% positive cells. Based on the CDK9 expression scores of the primary endometrial cancer samples, patients were divided into the following two groups: Low CDK9 group (CDK9 staining score ≤2) and high CDK9 group (CDK9 staining score ≥3).

Statictics: average;Range

Cohort age: 60.8;39-69

Funtion description: Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with the inhibitor suppressed cell proliferation and promoted apoptosis in endometrial cancer.

Funtion Uniprot: Protein kinase involved in the regulation of transcription (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094, PubMed:29335245). Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094). This complex is inactive when in the 7SK snRNP complex form (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094). Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR and the negative elongation factors DSIF and NELFE (PubMed:9857195, PubMed:10912001, PubMed:11112772, PubMed:12037670, PubMed:20081228, PubMed:20980437, PubMed:21127351). Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling) (PubMed:17956865, PubMed:18362169). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis (PubMed:10393184, PubMed:11112772). P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export (PubMed:15564463, PubMed:19575011, PubMed:19844166). Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing (PubMed:15564463, PubMed:19575011, PubMed:19844166). The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro (PubMed:21127351). Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage (PubMed:20493174). In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6 (PubMed:20493174). Promotes cardiac myocyte enlargement (PubMed:20081228). RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription (PubMed:21127351). AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect (PubMed:9857195, PubMed:10912001, PubMed:11112772). The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation (PubMed:12037670). Catalyzes phosphorylation of KAT5, promoting KAT5 recruitment to chromatin and histone acetyltransferase activity (PubMed:29335245).

UniProt ID: P50750

UniProt Link: https://www.uniprot.org/uniprotkb/P50750/entry

Biological function from UniProt: #DNA damage #DNA repair #Transcription #Transcription regulation

Molecular function from UniProt:

Tissue specificity from UniProt: Ubiquitous.

Subcellular UniProt: #Cytoplasm #Nucleus

Alternative name from UniProt:

Miscellaneous: CDK9 inhibition contributes to the anticancer activity of most CDK inhibitors under clinical investigation (PubMed:18423896 and PubMed:21779453). As a retroviruses target during the hijack of host transcription (e.g. HIV), CDK9 inhibitors might become specific antiretroviral agents (PubMed:18423896). May be a target for cardiac hypertrophy future treatments (PubMed:19757441 and PubMed:18423896). May also be a target in anti-inflammatory therapy in innate immunity and systemic inflammation (PubMed:18728388)

Catalytic activity: ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein];ATP + L-threonyl-[protein] = ADP + H+ + O-phospho-L-threonyl-[protein];[DNA-directed RNA polymerase] + ATP = ADP + H+ + phospho-[DNA-directed RNA polymerase];

Activity regulation: Inhibited by CDKI-71, CR8, GPC-286199, AG-024322, flavopiridol (alvocidib), RBG-286147, anilinopyrimidine 32, arylazopyrazole 31b, indirubin 3'-monoxime, meriolin 3,P276-00, olomoucine II, pyrazolotriazine, meriolin, variolin, thiazolyl-pyrimidine, thiazolyl-pyrimidine, indirubin-30-monoxime, ZK 304709, AG-012986, AT7519, R547, RGB-286638, imidazole pyrimidine, EXEL-3700, EXEL-8647, 5,6-dichloro-1-b-ribofur-anosyl-benzimidazole (DRB), P276-00, roscovitine (seliciclib, CYC202) and SNS-032 (BMS-387032). Activation by Thr-186 phosphorylation is calcium Ca2+ signaling pathway-dependent; actively inactivated by dephosphorylation mediated by PPP1CA, PPM1A and PPM1B. Reversibly repressed by acetylation at Lys-44 and Lys-48.

Gene name from HGNC: CDK9 (C-2k, CDC2L4, PITALRE, TAK)

CD antigen name: C-2K,Cell division cycle 2-like protein kinase 4 Cell division protein kinase 9 Serine/threonine-protein kinase PITALRE Tat-associated kinase complex catalytic subunit

HPA class: Disease related genes Enzymes Metabolic proteins Plasma proteins Potential drug targets

AlphaFold DB: P50750

AlphaFold Link: https://alphafold.ebi.ac.uk/entry/P50750

Induction: By replication stress, in chromatin. Probably degraded by the proteasome upon Thr-186 dephosphorylation.

HPA link: https://www.proteinatlas.org/ENSG00000136807-CDK9

Tissue specificity RNA from HPA: Low tissue specificity

Tissue expression from HPA: Ubiquitous nuclear expression.

Single cell type specificity Plasmacytoid DCs - Unknown function (mainly)

Immune cell specificity: Low immune cell specificity

Subcellular summary HPA Located in Nucleoplasm, Cytoplasmic bodies (Single cell variability)

Cancer prognostic summary HPA Prognostic marker in renal cancer (unfavorable)

Pathology link: https://www.proteinatlas.org/ENSG00000136807-CDK9/pathology

Pathology endo: https://www.proteinatlas.org/ENSG00000136807-CDK9/pathology/endometrial+cancer

Expression figure legend: Different CDK9 staining intensities and H&E staining of endometrial cancer tissues

Expression figure link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551504/figure/f1-or-44-05-1929/

Survival figure legend: Higher expression of CDK9 is present in metastatic and recurrent endometrial cancer tissues compared with that found in the patient matched primary tumors and CDK9 is correlated with poor patient prognosis.

Survival curve link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551504/figure/f2-or-44-05-1929/

Disease: No disease ID

Note1: Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy and confers predisposition to heart failure

OMIM: 603251

OMIM link2: https://www.omim.org/entry/603251

HGNC ID: HGNC:1780

HGNC link: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:1780