Protein kinase, membrane‑associated tyrosine/threonine�1 is associated with the progression of colorectal cancer

Abstract

The protein kinase, membrane‑associated tyrosine/threonine 1 (PKMYT1) is known to inhibit precocious entry into mitosis by phosphorylating CDK1 at Thr14 and Tyr15 residues. However, the functional importance of PKMYT1 in colorectal cancer (CRC) remains unknown. Thus, it is important to elucidate whether PKYMT1 is indispensable in the tumorigenesis of CRC. To investigate the functional importance of PKMYT1 in CRC tumorigenesis, PKMYT1 was knocked down in CRC cell lines such as SW480, SW620, HCT116 and HT29 by siRNA. PKMYT1‑depleted CRC cells were analyzed to determine proliferation, migration, invasion and colony forming ability. In addition, 179 patient‑derived samples were used to find the correlation of the expression of PKMYT1 with the prognosis of CRC patients. By siRNA‑mediated loss of function of PKMYT1, we observed that proliferation, migration, invasion and colony forming ability of CRC cell lines were significantly impaired in the absence of PKMYT1 in vitro. Furthermore, by analyzing patient‑derived samples, we revealed the association of PKMYT1 with the overall survival rate of CRC patients. These results indicated that PKMYT1 plays an essential oncogenic role in CRC and could serve as a good therapeutic target for the treatment of CRC.

A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target

“…2 ): (i) the high proliferation rate of cancer cells that follows the activation of driver oncogenes (e.g. RAS, MYC) needs to be sustained by a strong cell cycle regulation machinery; (ii) cancer cells frequently inactivate p53, which is a key gatekeeper of G0/G1 and S phases and, as a consequence, the regulation of cell cycle is sustained entirely by the G2/M checkpoint; (iii) the over-expression of DDR-related kinases is fundamental to maintain a tolerable level of genetic instability, an intrinsic feature of cancer cells [ 31 , 32 ]. Therefore, we can speculate that, once the malignant transformation process has been induced, WEE1 upregulation exerts a pro-tumorigenic functions by securing a tolerable level of genomic instability to cancer cells.…”

“…WEE1 and PKMYT1 are also over-expressed in solid tumors, including hepatocellular carcinoma, colon cancer, glioblastoma, non-small-cell lung cancer (NSCLS), neuroblastoma, and gastric cancers [ 31 , 32 , 45 – 47 ]. High WEE1 expression has been associated with negative prognostic factors including lymph node involvement, induction of metastasis, increased biomarkers of proliferation (CCND1, Ki67, or CCNA1) and resistance to treatments (radiotherapy or chemotherapy) [ 48 – 51 ].…”

“…In melanoma cells, WEE1 silencing caused an increase of phospho p38 protein levels, indicating a role in the regulation of p38/MAPK pathway activation during p53-independent DNA damage response [ 49 ]. In hepatocellular carcinoma and colorectal cancers, PKMYT1 regulates epithelial-mesenchymal transition (EMT), a process relevant to tumor progression, invasion, metastasis, and drug resistance, through the activation of the beta-catenin/TCF signaling [ 32 , 46 ], while PKMYT1 has been reported to control Notch pathway in NSCLC [ 45 ]. In particular, crucial component of the pathway, including NOTCH1, p21, and HES1 are downregulated by chemical inhibition of PKMYT1 [ 45 ].…”

“… [ 48 – 51 , 56 – 60 ] Mutation PA Insertion causing decrease WEE1 expression upon DNA damage [ 33 ] PKMYT1 Over-expression HC; CC; GLB; NSCLC; N; GS Associated with tumor progression, aggressive disease and poor overall survival. [ 31 , 32 , 45 – 47 ] Mutation N Biological effect or prognostic value unknown [ 61 ] ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, MM multiple myeloma, CML chronic myeloid leukemia, CLL chronic lymphocyte leukemia, DLBCL diffuse large B cell lymphoma, GC gastric cancer, MaM malignant melanoma, GL gliomas, OC ovarian cancer, CC colorectal cancer, PA pancreatic adenocarcinoma, HC hepatocellular carcinoma, GLB glioblastoma, NSCLC non-small-cell lung cancer, N neuroblastoma …”

Systematic expression analysis of WEE family kinases reveals the importance of PKMYT1 in breast carcinogenesis

“…Research on the pathogenesis, diagnosis and treatment of breast cancer remains an area of active investigation 43. This study was the first to investigate the mRNA expression and prognosis of PKMYT1 in breast cancer, although other studies have reported PKMYT1 alternations in the occurrence and development of several cancers, including liver 44 and colorectal carcinomas 45. As the key regulators of G2/M transition, WEE family kinases play essential role in maintaining cell genomic stability under rapid cell proliferation.…”