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HYSK1 promotes cancer cell proliferation and migration through negative regulation of p16INK4a under hypoxic conditions.

ABSTRACT: The alteration of expression of p16INK4a, a well-known cyclin-dependent kinase inhibitor involved in cell cycle control, in tumors is unclear, especially under hypoxic conditions. To evaluate p16INK4a regulation, we performed a protein microarray analysis. Among 1,800 proteins in the array, we identified hYSK1 as a novel protein that interacts with the tumor suppressor p16INK4a. hYSK1, a member of the Ste20 family of serine/threonine protein kinases, promotes cell migration and tumorigenesis and is activated by oxidative stress. However, the molecular mechanisms underlying the oncogenic potential of hYSK1 remain elusive. Here, we report that hYSK1 interacts with p16INK4a under hypoxic conditions in tumors, where it negatively regulates p16INK4a, enhancing cancer cell migration. Hypoxic stimulation of hYSK1 reduces p16INK4a accumulation through p16 promoter regulation to interact with unphosporylated SP-1 and increases matrix metalloproteinase-2 (MMP-2) expression by activating the MMP-2 promoter associated with cell migration and proliferation.Conversely, knocking down hYSK1 expression activated p16INK4a expression and suppressed MMP-2 expression. Thus, hYSK1 is necessary as a trigger for inactivating p16INK4a and activating MMP-2 during tumor migration, suggesting that hYSK1 is a specific negative regulator of the tumor suppressor p16INK4a and may represent a novel molecular target for reactivation of tumor suppressor genes in humans.

SUBMITTER: Lee MH

PROVIDER: S-EPMC5687670 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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hYSK1 promotes cancer cell proliferation and migration through negative regulation of p16INK4a under hypoxic conditions.

Lee Mee-Hyun MH Dong Zigang Z Surh Young-Joon YJ Choi Bu Young BY

Oncotarget 20171006 51

The alteration of expression of p16INK4a, a well-known cyclin-dependent kinase inhibitor involved in cell cycle control, in tumors is unclear, especially under hypoxic conditions. To evaluate p16INK4a regulation, we performed a protein microarray analysis. Among 1,800 proteins in the array, we identified hYSK1 as a novel protein that interacts with the tumor suppressor p16INK4a. hYSK1, a member of the Ste20 family of serine/threonine protein kinases, promotes cel ...[more]

PMID: 29179500

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Project description:BackgroundSelf-sampling for human papillomavirus (HPV) testing is a feasible option to improve the cervical screening coverage. However, an ideal triage method for HPV-positive self-samples does not yet exist. The aim of this study was to explore the utility of HPV genotyping and p16INK4a immunostaining (p16) in triaging HPV-positive self-samples, focusing on HPV-positive, cytology-negative (HPCN) women.MethodsA total of 73,699 women were screened in a cervical screening project in China via SeqHPV assay on self-samples. HPV-positive women were called-back and collected cervical sample for p16 immunostaining and liquid-based cytology, those who met any result of HPV16/18+ or visual inspection with acetic acid (VIA) + or p16+ were referred for colposcopy, and HPCN women with adequate data on p16 and pathology were analyzed. A triage strategy was considered acceptable if the negative predictive value (NPV) for cervical intraepithelial neoplasia 3 or worse (CIN3+) was 98% or more, combined with an improvement of sensitivity and specificity for CIN2+/CIN3+ in reference to the comparator, being HPV16/18 + .ResultsA total of 2731 HPCN women aged 30-64 years were enrolled, 136 (5.0%) CIN2+ and 53 (1.9%) CIN3+ were detected. Five triage strategies met the criteria: p16+; HPV16/33+; 'HPV16+ or HPV33/58/31/35+&p16+'; 'HPV16/33+ or HPV58/31/35+&p16+'; HPV16/18/31/33/45/52/58 + & p16+. These strategies required less or similar colposcopy referrals, and less colposcopies to detected one case of CIN2+/CIN3+, achieving favorable false positive (negative) rates to the comparator. Among them, p16 staining detected 83.1% (79.2%) of underlying CIN2 + (CIN3+) in HPCN women. Moreover, three triage strategies were favorable in sensitivity and/or specificity to the 'HPV16/33+' strategy: p16+; 'HPV16+ or HPV33/58/31/35 + &p16+'; HPV16/18/31/33/45/52/58 + &p16 + .ConclusionsGenotyping for HPV16/33 could be utilized to optimize the management of HPCN women. Moreover, p16 immunostaining, either alone or combined with extended genotypes, is more effective than HPV genotypes alone in the triage of HPCN women.

Dataset Information

HYSK1 promotes cancer cell proliferation and migration through negative regulation of p16INK4a under hypoxic conditions.

Publications

hYSK1 promotes cancer cell proliferation and migration through negative regulation of p16<sup>INK4a</sup> under hypoxic conditions.

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