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KDM6A addiction of cervical carcinoma cell lines is triggered by E7 and mediated by p21CIP1 suppression of replication stress

Soto, David R., Barton, Christopher, Munger, Karl, McLaughlin-Drubin, Margaret E.·2017·PLOS Pathogens
DOI 10.1371/journal.ppat.1006661PMC PMC5638616
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Fig 1 High-risk, but not low-risk HPV E7 proteins induce KDM6A expression. (A) Quantitative real-time RT-PCR analysis of KDM6A mRNA expression in HFK and HFK/E7 cells. (B) Absolute quantification of HPV E7 mRNA expression in HFK and HFK/E7 cells. (C) Quantitative real-time RT-PCR analysis of KDM6A mRNA expression in HFK cells, the HPV16 positive CaSki and SiHa cervical carcinoma cell lines, the HPV39 positive cervical cancer cell line Me-180, and the HPV18 positive cervical cancer cell line HeLa. The bar graphs show averages and SDs from three independent experiments, each performed in triplicate. Increases in HPV16 and 18 E7 expressing cells and the HPV positive CaSki, SiHa, Me-180, and HeLa cells are statistically significant (**), with P values < 0.01.
Fig 1 High-risk, but not low-risk HPV E7 proteins induce KDM6A expression. (A) Quantitative real-time RT-PCR analysis of KDM6A mRNA expression in HFK and HFK/E7 cells. (B) Absolute quantification of HPV E7 mRNA expression in HFK and HFK/E7 cells. (C) Quantitative real-time RT-PCR analysis of KDM6A mRNA expression in HFK cells, the HPV16 positive CaSki and SiHa cervical carcinoma cell lines, the HPV39 positive cervical cancer cell line Me-180, and the HPV18 positive cervical cancer cell line HeLa. The bar graphs show averages and SDs from three independent experiments, each performed in triplicate. Increases in HPV16 and 18 E7 expressing cells and the HPV positive CaSki, SiHa, Me-180, and HeLa cells are statistically significant (**), with P values < 0.01.CC BY · PubMed Central
Fig 2 KDM6A addiction is caused by the HPV E7 protein. (A,B) KDM6A was depleted in the HPV16 positive SiHa and CaSki cervical carcinoma cell lines, the HPV39 positive cervical cancer cell line Me-180, and the HPV18 positive cervical cancer cell line HeLa; (A) Cell viability was measured by reduction of resazurin. Three independent KDM6A shRNA constructs (60, 61, and 62) were used in the initial experiments in SiHa cells; (B) KDM6A depletion was verified by quantitative real-time RT-PCR; (C-F). KDM6A was depleted in HFKs expressing control vector, HPV16 E7, E6, or E6 and E7; (C) Cell viability was measured by reduction of resazurin; (D) HPV E7 expression was verified by quantitative real-time RT-PCR and compared to levels found in SiHa and CaSki cervical carcinoma cells; (E) Due to the absence of appropriate antibodies, HPV16 E6 expression was determined by assessing p53 levels, which are decreased in HPV16 E6-expressing cells because of E6-mediated proteasomal degradation [66], by Western blot analysis of p53. Lysates were separated by SDS/PAGE, transferred, and probed for p53. An actin blot is included as a loading control; (F) KDM6A depletion was verified by quantitative real-time RT-PCR; (G-I) KDM6A was depleted in HFKs expressing HPV6, HPV11, or HPV18 E7; (G) Cell viability was measured by reduction of resazurin; (H) HPV6 E7, HPV11 E7, and HPV18 E7 mRNA levels were determined by qRT-PCR; (I) KDM6A depletion was verified by quantitative real-time RT-PCR; (J,K) KDM6A was depleted in U2OS-tet on cells with doxycycline-inducible expression of HPV16 E7 using a KDM6A shRNA construct or KDMA6A-specific siRNA duplexes. (J). Cell viability was measured by reduction of resazurin; (K) Western blot analysis of HPV16 E7 and KDM6A. Lysates were separated by SDS/PAGE, transferred, and probed for HPV16 E7 and KDM6A. An actin blot is included as a loading control; (L) KDM6A was depleted in the HPV16 positive SiHa cervical carcinoma cell line. After 10 days of puromycin selection, live cells were stained with sulforhodamine B; and (M) Cell cycle profile determined by fluorescence-activated sorting from a representative experiment and percentage of sub-G1 phase from three independent experiments. Averages and SDs for three independent experiments are shown. Statistically significant changes are indicated, **P < 0.01.
Fig 2 KDM6A addiction is caused by the HPV E7 protein. (A,B) KDM6A was depleted in the HPV16 positive SiHa and CaSki cervical carcinoma cell lines, the HPV39 positive cervical cancer cell line Me-180, and the HPV18 positive cervical cancer cell line HeLa; (A) Cell viability was measured by reduction of resazurin. Three independent KDM6A shRNA constructs (60, 61, and 62) were used in the initial experiments in SiHa cells; (B) KDM6A depletion was verified by quantitative real-time RT-PCR; (C-F). KDM6A was depleted in HFKs expressing control vector, HPV16 E7, E6, or E6 and E7; (C) Cell viability was measured by reduction of resazurin; (D) HPV E7 expression was verified by quantitative real-time RT-PCR and compared to levels found in SiHa and CaSki cervical carcinoma cells; (E) Due to the absence of appropriate antibodies, HPV16 E6 expression was determined by assessing p53 levels, which are decreased in HPV16 E6-expressing cells because of E6-mediated proteasomal degradation [66], by Western blot analysis of p53. Lysates were separated by SDS/PAGE, transferred, and probed for p53. An actin blot is included as a loading control; (F) KDM6A depletion was verified by quantitative real-time RT-PCR; (G-I) KDM6A was depleted in HFKs expressing HPV6, HPV11, or HPV18 E7; (G) Cell viability was measured by reduction of resazurin; (H) HPV6 E7, HPV11 E7, and HPV18 E7 mRNA levels were determined by qRT-PCR; (I) KDM6A depletion was verified by quantitative real-time RT-PCR; (J,K) KDM6A was depleted in U2OS-tet on cells with doxycycline-inducible expression of HPV16 E7 using a KDM6A shRNA construct or KDMA6A-specific siRNA duplexes. (J). Cell viability was measured by reduction of resazurin; (K) Western blot analysis of HPV16 E7 and KDM6A. Lysates were separated by SDS/PAGE, transferred, and probed for HPV16 E7 and KDM6A. An actin blot is included as a loading control; (L) KDM6A was depleted in the HPV16 positive SiHa cervical carcinoma cell line. After 10 days of puromycin selection, live cells were stained with sulforhodamine B; and (M) Cell cycle profile determined by fluorescence-activated sorting from a representative experiment and percentage of sub-G1 phase from three independent experiments. Averages and SDs for three independent experiments are shown. Statistically significant changes are indicated, **P < 0.01.CC BY · PubMed Central
Fig 3 KDM6A addiction is KDM6B-independent. (A, B) KDM6A was depleted, and KDM6A, KDM6B, or p16INK4A was expressed in the HPV16 positive CaSki cervical cancer line; (A) Cell viability was measured by reduction of resazurin; (B) Depletion and expression were verified by quantitative real-time RT-PCR; (C,D) CDK4 and CDK6 were depleted by transfection with CDK4- and CDK6-specific siRNA duplexes in the HPV16 positive CaSki cervical carcinoma cell line; (C) Cell viability was measured by reduction of resazurin; (D) Depletion was verified by quantitative real-time RT-PCR, Averages and SDs for three independent experiments are shown. Statistically significant changes are indicated, **P < 0.01.
Fig 3 KDM6A addiction is KDM6B-independent. (A, B) KDM6A was depleted, and KDM6A, KDM6B, or p16INK4A was expressed in the HPV16 positive CaSki cervical cancer line; (A) Cell viability was measured by reduction of resazurin; (B) Depletion and expression were verified by quantitative real-time RT-PCR; (C,D) CDK4 and CDK6 were depleted by transfection with CDK4- and CDK6-specific siRNA duplexes in the HPV16 positive CaSki cervical carcinoma cell line; (C) Cell viability was measured by reduction of resazurin; (D) Depletion was verified by quantitative real-time RT-PCR, Averages and SDs for three independent experiments are shown. Statistically significant changes are indicated, **P < 0.01.CC BY · PubMed Central
Fig 4 KDM6A addiction is mediated by p21CIP1. (A-C) p21CIP1 was depleted in the HPV16 positive CaSki and SiHa cervical carcinoma cell lines, and the HPV39 positive Me-180 cervical cancer line. Six independent p21CIP1 shRNA constructs (123, 125, 126, 127, 400, and 401) were used in the initial experiments in the CaSki cell line and two independent p21CIP1 shRNA expression vectors (123 and 127) were used in the SiHa and Me-180 cell lines; (A) Cell viability was measured by reduction of resazurin; (B) p21CIP1 depletion in the CaSki cell line was verified by Western blot. Lysates were separated by SDS/PAGE, transferred, and probed for p21CIP1. An actin blot is included as a loading control; (C) p21CIP1 depletion in the SiHa and Me-180 cell lines was verified by quantitative real-time RT-PCR; (D,E) p21CIP1 was depleted in HFKs expressing HPV6, HPV11, HPV16, and HPV18 E7; (D) Cell viability was measured by reduction of resazurin; (E) p21CIP1 depletion was verified by quantitative real-time RT-PCR; (F,G) p21CIP1 was depleted in U2OS-tet on cells with doxycycline-inducible expression of HPV16 E7; (F) Cell viability was measured by reduction of resazurin; (G) p21CIP1 depletion was verified by Western blot. Lysates were separated by SDS/PAGE, transferred, and probed for p21CIP1. An actin blot is included as a loading control; (H) p21CIP1 was depleted in the HPV16 positive SiHa cervical carcinoma cell line. After 10 days of puromycin selection, live cells were stained with sulforhodamine B. The bar graph depicts the percentages of live cells averaged from three experiments; (I) Cell cycle profile determined by fluorescence-activated sorting from a representative experiment and percentage of sub-G1 phase from three independent experiments; (J,K) KDM6A was depleted and p21CIP1 was expressed in the HPV16 positive CaSki cervical carcinoma cell line; (J) Cell viability was measured by reduction of resazurin; (K) Depletion and expression were verified by immunoblotting. Lysates were separated by SDS/PAGE, transferred, and probed for KDM6A and p21CIP1. An actin blot is included as a loading control; (L,M) KDM6B was depleted and p21CIP1 was expressed in the HPV16 positive CaSki cervical carcinoma cell line; (L) Cell viability was measured by reduction of resazurin; (M) Depletion and expression were verified by immunoblotting. Lysates were separated by SDS/PAGE, transferred, and probed for KDM6B and p21CIP1. An actin blot is included as a loading control; (N) KDM6A was depleted in the HPV16 positive CaSki cervical carcinoma cells and p21CIP1 expression was analyzed by Western blotting at 72 h post-transfection. An actin blot is shown as a loading control. (O) ChIP assays using lysates from SiHa cells using an antibody specific for H3K27me3 or the negative control IgG. qPCR was used to measure the degree of enrichment, and the results for each primer pair that captures sites at -4 kB and -2 kB in the p21CIP1 promoter are presented as a percentage of bound/input. Statistically significant changes (P < 0.05) are indicated by an asterisk. Fold enrichment over IgG was determined and is shown for each primer pair that capture sites at -4 kB and -2 kB in the p21CIP1 promoter. Averages and SDs for three independent experiments are shown. Statistically significant changes are indicated, **P < 0.01.
Fig 4 KDM6A addiction is mediated by p21CIP1. (A-C) p21CIP1 was depleted in the HPV16 positive CaSki and SiHa cervical carcinoma cell lines, and the HPV39 positive Me-180 cervical cancer line. Six independent p21CIP1 shRNA constructs (123, 125, 126, 127, 400, and 401) were used in the initial experiments in the CaSki cell line and two independent p21CIP1 shRNA expression vectors (123 and 127) were used in the SiHa and Me-180 cell lines; (A) Cell viability was measured by reduction of resazurin; (B) p21CIP1 depletion in the CaSki cell line was verified by Western blot. Lysates were separated by SDS/PAGE, transferred, and probed for p21CIP1. An actin blot is included as a loading control; (C) p21CIP1 depletion in the SiHa and Me-180 cell lines was verified by quantitative real-time RT-PCR; (D,E) p21CIP1 was depleted in HFKs expressing HPV6, HPV11, HPV16, and HPV18 E7; (D) Cell viability was measured by reduction of resazurin; (E) p21CIP1 depletion was verified by quantitative real-time RT-PCR; (F,G) p21CIP1 was depleted in U2OS-tet on cells with doxycycline-inducible expression of HPV16 E7; (F) Cell viability was measured by reduction of resazurin; (G) p21CIP1 depletion was verified by Western blot. Lysates were separated by SDS/PAGE, transferred, and probed for p21CIP1. An actin blot is included as a loading control; (H) p21CIP1 was depleted in the HPV16 positive SiHa cervical carcinoma cell line. After 10 days of puromycin selection, live cells were stained with sulforhodamine B. The bar graph depicts the percentages of live cells averaged from three experiments; (I) Cell cycle profile determined by fluorescence-activated sorting from a representative experiment and percentage of sub-G1 phase from three independent experiments; (J,K) KDM6A was depleted and p21CIP1 was expressed in the HPV16 positive CaSki cervical carcinoma cell line; (J) Cell viability was measured by reduction of resazurin; (K) Depletion and expression were verified by immunoblotting. Lysates were separated by SDS/PAGE, transferred, and probed for KDM6A and p21CIP1. An actin blot is included as a loading control; (L,M) KDM6B was depleted and p21CIP1 was expressed in the HPV16 positive CaSki cervical carcinoma cell line; (L) Cell viability was measured by reduction of resazurin; (M) Depletion and expression were verified by immunoblotting. Lysates were separated by SDS/PAGE, transferred, and probed for KDM6B and p21CIP1. An actin blot is included as a loading control; (N) KDM6A was depleted in the HPV16 positive CaSki cervical carcinoma cells and p21CIP1 expression was analyzed by Western blotting at 72 h post-transfection. An actin blot is shown as a loading control. (O) ChIP assays using lysates from SiHa cells using an antibody specific for H3K27me3 or the negative control IgG. qPCR was used to measure the degree of enrichment, and the results for each primer pair that captures sites at -4 kB and -2 kB in the p21CIP1 promoter are presented as a percentage of bound/input. Statistically significant changes (P < 0.05) are indicated by an asterisk. Fold enrichment over IgG was determined and is shown for each primer pair that capture sites at -4 kB and -2 kB in the p21CIP1 promoter. Averages and SDs for three independent experiments are shown. Statistically significant changes are indicated, **P < 0.01.CC BY · PubMed Central
Fig 5 Rescue of KDM6A addiction by p21CIP1 is dependent on the integrity of the PCNA binding site. (A,B) Ectopic expression of the CDK2 inhibitor p27KIP1, which lacks PCNA interaction, does not rescue loss of KDM6A or p21CIP1 KDM6A or p21CIP1 were depleted in the HPV16-positive CaSki cervical carcinoma cell line and p27 was expressed; (A) Cell viability was measured by reduction of resazurin; (B) Depletion and expression were verified by quantitative real-time RT-PCR; (C,D) Ectopic expression of the C-terminal PCNA domain of p21CIP1 rescues KDM6A addiction, whereas expression of the N-terminal CDK2 inhibitor domain of p21CIP1, a PCNA binding defective p21CIP1 mutant, or a dominant negative mutant fails to rescue; C) Cell viability was measured by reduction of resazurin; (D) Expression was verified by immunoblot. Lysates were separated by SDS/PAGE, transferred, and probed p21CIP1. An actin blot is included as a loading control. Experiments were performed in CaSki cells, bars indicate averages and SDs of three experiments. Statistically significant changes are indicated, **P < 0.01.
Fig 5 Rescue of KDM6A addiction by p21CIP1 is dependent on the integrity of the PCNA binding site. (A,B) Ectopic expression of the CDK2 inhibitor p27KIP1, which lacks PCNA interaction, does not rescue loss of KDM6A or p21CIP1 KDM6A or p21CIP1 were depleted in the HPV16-positive CaSki cervical carcinoma cell line and p27 was expressed; (A) Cell viability was measured by reduction of resazurin; (B) Depletion and expression were verified by quantitative real-time RT-PCR; (C,D) Ectopic expression of the C-terminal PCNA domain of p21CIP1 rescues KDM6A addiction, whereas expression of the N-terminal CDK2 inhibitor domain of p21CIP1, a PCNA binding defective p21CIP1 mutant, or a dominant negative mutant fails to rescue; C) Cell viability was measured by reduction of resazurin; (D) Expression was verified by immunoblot. Lysates were separated by SDS/PAGE, transferred, and probed p21CIP1. An actin blot is included as a loading control. Experiments were performed in CaSki cells, bars indicate averages and SDs of three experiments. Statistically significant changes are indicated, **P < 0.01.CC BY · PubMed Central
Fig 6 Decrease in viability in response to KDM6A/p21CIP1 depletion in E7 expressing cells may be a consequence of replication stress. (A,B) Depletion of the CDC7/DBF4 kinase rescues KDM6A loss. Each shKDM6A + shCDC7 + shDBF4 depletion contained shKDM6A 60 and the following combinations of shCDC7 and shDBF4, in order: shCDC7 168/shDBF4 954, shCDC7 169/shDBF4 955, shCDC7 170/shDBF4 956, shCDC7 171/shDBF4 957, shCDC7 169/shDBF4 954, and shCDC7 172/shDBF4 957; (A) Cell viability was measured by reduction of resazurin; (B) Depletion was verified by quantitative real-time RT-PCR; (C,D) CDT1 depletion rescues KDM6A and p21CIP1 loss; (C) Cell viability was measured by reduction of resazurin; (B) Depletion was verified by quantitative real-time RT-PCR; (E,F) Supplementing E7 expressing CaSki cells with exogenous nucleosides inhibits cell death in response to p21CIP1 depletion. p21CIP1 was depleted in U2OS osteosarcoma cells with doxycycline-inducible HPV16 E7 expression and supplemented with 50 μM nucleosides in the media or grown under standard conditions; (E) Cell viability was measured by reduction of resazurin; (F) Depletion was verified by immunoblot. Lysates were separated by SDS/PAGE, transferred, and probed p21CIP1. An actin blot is included as a loading control. Bar graphs represent averages and SDs of three experiments, statistically significant changes are indicated, **P < 0.01.
Fig 6 Decrease in viability in response to KDM6A/p21CIP1 depletion in E7 expressing cells may be a consequence of replication stress. (A,B) Depletion of the CDC7/DBF4 kinase rescues KDM6A loss. Each shKDM6A + shCDC7 + shDBF4 depletion contained shKDM6A 60 and the following combinations of shCDC7 and shDBF4, in order: shCDC7 168/shDBF4 954, shCDC7 169/shDBF4 955, shCDC7 170/shDBF4 956, shCDC7 171/shDBF4 957, shCDC7 169/shDBF4 954, and shCDC7 172/shDBF4 957; (A) Cell viability was measured by reduction of resazurin; (B) Depletion was verified by quantitative real-time RT-PCR; (C,D) CDT1 depletion rescues KDM6A and p21CIP1 loss; (C) Cell viability was measured by reduction of resazurin; (B) Depletion was verified by quantitative real-time RT-PCR; (E,F) Supplementing E7 expressing CaSki cells with exogenous nucleosides inhibits cell death in response to p21CIP1 depletion. p21CIP1 was depleted in U2OS osteosarcoma cells with doxycycline-inducible HPV16 E7 expression and supplemented with 50 μM nucleosides in the media or grown under standard conditions; (E) Cell viability was measured by reduction of resazurin; (F) Depletion was verified by immunoblot. Lysates were separated by SDS/PAGE, transferred, and probed p21CIP1. An actin blot is included as a loading control. Bar graphs represent averages and SDs of three experiments, statistically significant changes are indicated, **P < 0.01.CC BY · PubMed Central
Fig 7 KDM6A/p21CIP1 depletion in E7 expressing cells causes 53BP1 nuclear foci formation. KDM6A or p21CIP1 were depleted in the HPV16 positive SiHa cervical carcinoma cells. (A) The cells were immunostained with an antibody against 53BP1; (B) 53BP1 nuclear foci in 100 cells per experiment were quantified; and (C) Quantification of 53BP1 nuclear foci per nucleus upon KDM6A/p21CIP1 depletion. Bar graphs represent averages and SDs of six experiments, statistically significant changes are indicated, **P < 0.01.
Fig 7 KDM6A/p21CIP1 depletion in E7 expressing cells causes 53BP1 nuclear foci formation. KDM6A or p21CIP1 were depleted in the HPV16 positive SiHa cervical carcinoma cells. (A) The cells were immunostained with an antibody against 53BP1; (B) 53BP1 nuclear foci in 100 cells per experiment were quantified; and (C) Quantification of 53BP1 nuclear foci per nucleus upon KDM6A/p21CIP1 depletion. Bar graphs represent averages and SDs of six experiments, statistically significant changes are indicated, **P < 0.01.CC BY · PubMed Central
Fig 8 KDM6A/p21CIP1 depletion in E7 expressing cells causes re-replication. KDM6A or p21CIP1 were depleted in the HPV16 positive SiHa cervical carcinoma cells. Example of single combed DNA molecules labeled with IdU (green) and CldU (red).
Fig 8 KDM6A/p21CIP1 depletion in E7 expressing cells causes re-replication. KDM6A or p21CIP1 were depleted in the HPV16 positive SiHa cervical carcinoma cells. Example of single combed DNA molecules labeled with IdU (green) and CldU (red).CC BY · PubMed Central
Fig 9 The p21CIP1 regulatory circuit in normal (A) high-risk HPV E6/E7 expressing cells (B), and high-risk HPV E6/E7 expressing cells depleted of KDM6A and/or p21CIP1 (C). See text for details.
Fig 9 The p21CIP1 regulatory circuit in normal (A) high-risk HPV E6/E7 expressing cells (B), and high-risk HPV E6/E7 expressing cells depleted of KDM6A and/or p21CIP1 (C). See text for details.CC BY · PubMed Central

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Cited by

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Metadata

Authors
Soto, D. R., Barton, C., Munger, K., & McLaughlin-Drubin, M. E.
Venue
PLOS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2017-10-02
Volume
13
Issue
10
Pages
e1006661
ISSN
1553-7374
DOI
10.1371/journal.ppat.1006661
PMC
PMC5638616
Cited by
39
References
9
Language
en
Update notices
new_version (2017-10-12)
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • American Cancer Society (126540-RSG-14-203-01-MPC)
  • National Cancer Institute (CA066980)

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