As we have discussed in the preceding chapters, the regulation of gene expression in higher eukaryotes is a highly complex process. It is not surprising, therefore, that this process can go wrong. Indeed, the identification of the molecular basis of many human diseases has shown some to be due to defects in gene regulation.
Multiple-choice questions
Questions for Discussion
- The curve of lung cancer deaths parallels the per capita cigarette consumption curve, but the curve for lung cancer deaths appears about 25 years later than the curve for cigarette smoking. Discuss the reasons for this delay and refute the argument that smokers are inherently more susceptible to cancer and that cigarettes have no relation to lung cancer.
- Cancer can result from either the activation of a gene that stimulates cell growth or the inactivation of a gene that inhibits it. Gene X, which is frequently mutated in human brain cancers, is a newly discovered gene. It encodes a protein that binds to another protein, Y, increasing its affinity for the degradation complex. When Y protein levels are excessive, it enters the nucleus and activates genes essential for cell proliferation. Based on this information, which category (oncogene or tumor suppressor) does genes X and Y belong to? Explain your answer and how many copies of X and Y need to be mutated to trigger uncontrolled cell proliferation.
- The Rb gene belongs to a class of genes known as tumor suppressors that inhibit cell growth, yielding an antiproliferative effect. Loss of both copies of these genes often results in the development of cancer. As a potential cancer vaccine approach, could elevating the expression levels of tumor suppressor genes like Rb in all cells eradicate cancer? What would be the implications for human health? Explain your answers.
- The ARF protein is an inhibitor of Mdm2, which, in turn, inhibits the tumor suppressor gene p53. The Myc oncogene, in addition to stimulating cell-proliferation pathways, also activates ARF, thereby indirectly influencing the activity of p53. Based on this information, what would you predict the formation of cancers in ARF+/– vs ARF+/+ mice? Explain your answer.
- The Myc protein is commonly overexpressed in cancer cells, promoting an increase in cell growth and division. Conversely, in normal cells, excessive Myc expression typically leads to cell-cycle arrest or apoptosis. Explain how overexpression of Myc can have such distinct impacts on normal and cancer cells.
Further Reading
13.1 Gene regulation and cancer
Dhanasekaran, R., Deutzmann, A., Mahauad-Fernandez, W. D., Hansen, A. S., Gouw, A. M., & Felsher, D. W. (2022). The MYC oncogene—The grand orchestrator of cancer growth and immune evasion. Nature Reviews. Clinical Oncology, 19(1), 23–36. https://doi.org/10.1038/s41571-021-00549-2
Glenfield, C., & Innan, H. (2021). Gene Duplication and Gene Fusion Are Important Drivers of Tumourigenesis during Cancer Evolution. Genes, 12(9), 1376. https://doi.org/10.3390/genes12091376
Lipsick, J. (2022). A History of Cancer Research: Retroviral Oncogenes. Cold Spring Harbor Perspectives in Medicine, 12(4), a035865. https://doi.org/10.1101/cshperspect.a035865
Lourenco, C., Resetca, D., Redel, C., Lin, P., MacDonald, A. S., Ciaccio, R., Kenney, T. M. G., Wei, Y., Andrews, D. W., Sunnerhagen, M., Arrowsmith, C. H., Raught, B., & Penn, L. Z. (2021). MYC protein interactors in gene transcription and cancer. Nature Reviews. Cancer, 21(9), 579–591. https://doi.org/10.1038/s41568-021-00367-9
Martínez-Jiménez, F., Muiños, F., Sentís, I., Deu-Pons, J., Reyes-Salazar, I., Arnedo-Pac, C., Mularoni, L., Pich, O., Bonet, J., Kranas, H., Gonzalez-Perez, A., & Lopez-Bigas, N. (2020). A compendium of mutational cancer driver genes. Nature Reviews. Cancer, 20(10), 555–572. https://doi.org/10.1038/s41568-020-0290-x
Ramsden, D. A., & Nussenzweig, A. (2021). Mechanisms driving chromosomal translocations: Lost in time and space. Oncogene, 40(25), 4263–4270. https://doi.org/10.1038/s41388-021-01856-9
Tanaka, H., & Watanabe, T. (2020). Mechanisms Underlying Recurrent Genomic Amplification in Human Cancers. Trends in Cancer, 6(6), 462–477. https://doi.org/10.1016/j.trecan.2020.02.019
Taniue, K., & Akimitsu, N. (2021). Fusion Genes and RNAs in Cancer Development. Non-Coding RNA, 7(1), 10. https://doi.org/10.3390/ncrna7010010
Weinberg, R. A. (2013). The Biology of Cancer (2nd ed.). W.W. Norton & Company. https://doi.org/10.1201/9780429258794
13.2 Oncogenic transcription factors
Baluapuri, A., Wolf, E., & Eilers, M. (2020). Target gene-independent functions of MYC oncoproteins. Nature Reviews. Molecular Cell Biology, 21(5), 255–267. https://doi.org/10.1038/s41580-020-0215-2
Bejjani, F., Evanno, E., Zibara, K., Piechaczyk, M., & Jariel-Encontre, I. (2019). The AP-1 transcriptional complex: Local switch or remote command? Biochimica Et Biophysica Acta. Reviews on Cancer, 1872(1), 11–23. https://doi.org/10.1016/j.bbcan.2019.04.003
Castaneda, M., Hollander, P. den, & Mani, S. A. (2022). Forkhead Box Transcription Factors: Double-Edged Swords in Cancer. Cancer Research, 82(11), 2057–2065. https://doi.org/10.1158/0008-5472.CAN-21-3371
Hammouda, M. B., Ford, A. E., Liu, Y., & Zhang, J. Y. (2020). The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer. Cells, 9(4), 857. https://doi.org/10.3390/cells9040857
Huebner, K., Procházka, J., Monteiro, A. C., Mahadevan, V., & Schneider-Stock, R. (2019). The activating transcription factor 2: An influencer of cancer progression. Mutagenesis, 34(5–6), 375–389. https://doi.org/10.1093/mutage/gez041
13.3 Tumor suppressor transcription factors
Barnoud, T., Indeglia, A., & Murphy, M. E. (2021). Shifting the paradigms for tumor suppression: Lessons from the p53 field. Oncogene, 40(25), 4281–4290. https://doi.org/10.1038/s41388-021-01852-z
Datta, N., Chakraborty, S., Basu, M., & Ghosh, M. K. (2020). Tumor Suppressors Having Oncogenic Functions: The Double Agents. Cells, 10(1), 46. https://doi.org/10.3390/cells10010046
Engeland, K. (2022a). Cell cycle regulation: P53-p21-RB signaling. Cell Death and Differentiation, 29(5), 946–960. https://doi.org/10.1038/s41418-022-00988-z
Engeland, K. (2022b). Cell cycle regulation: P53-p21-RB signaling. Cell Death and Differentiation, 29(5), 946–960. https://doi.org/10.1038/s41418-022-00988-z
Ferragut Cardoso, A. P., Banerjee, M., Nail, A. N., Lykoudi, A., & States, J. C. (2021). miRNA dysregulation is an emerging modulator of genomic instability. Seminars in Cancer Biology, 76, 120–131. https://doi.org/10.1016/j.semcancer.2021.05.004
Groelly, F. J., Fawkes, M., Dagg, R. A., Blackford, A. N., & Tarsounas, M. (2023). Targeting DNA damage response pathways in cancer. Nature Reviews. Cancer, 23(2), 78–94. https://doi.org/10.1038/s41568-022-00535-5
Hatano, Y., Tamada, M., Matsuo, M., & Hara, A. (2020). Molecular Trajectory of BRCA1 and BRCA2 Mutations. Frontiers in Oncology, 10, 361. https://doi.org/10.3389/fonc.2020.00361
Jakoube, P., Cutano, V., González-Morena, J. M., & Keckesova, Z. (2021). Mitochondrial Tumor Suppressors-The Energetic Enemies of Tumor Progression. Cancer Research, 81(18), 4652–4667. https://doi.org/10.1158/0008-5472.CAN-21-0518
Kaiser, A. M., & Attardi, L. D. (2018). Deconstructing networks of p53-mediated tumor suppression in vivo. Cell Death and Differentiation, 25(1), 93–103. https://doi.org/10.1038/cdd.2017.171
Klein, A. M., de Queiroz, R. M., Venkatesh, D., & Prives, C. (2021). The roles and regulation of MDM2 and MDMX: It is not just about p53. Genes & Development, 35(9–10), 575–601. https://doi.org/10.1101/gad.347872.120
Rubin, S. M., Sage, J., & Skotheim, J. M. (2020). Integrating Old and New Paradigms of G1/S Control. Molecular Cell, 80(2), 183–192. https://doi.org/10.1016/j.molcel.2020.08.020
Wang, H., Yang, L., Liu, M., & Luo, J. (2023). Protein post-translational modifications in the regulation of cancer hallmarks. Cancer Gene Therapy, 30(4), 529–547. https://doi.org/10.1038/s41417-022-00464-3
13.4 The epigenome and cancer
Chang, S., Yim, S., & Park, H. (2019). The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: Crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Experimental & Molecular Medicine, 51(6), 1–17. https://doi.org/10.1038/s12276-019-0230-6
Eustermann, S., Patel, A. B., Hopfner, K.-P., He, Y., & Korber, P. (2024). Energy-driven genome regulation by ATP-dependent chromatin remodellers. Nature Reviews. Molecular Cell Biology, 25(4), 309–332. https://doi.org/10.1038/s41580-023-00683-y
Flaus, A., Downs, J. A., & Owen-Hughes, T. (2021). Histone isoforms and the oncohistone code. Current Opinion in Genetics & Development, 67, 61–66. https://doi.org/10.1016/j.gde.2020.11.003
Hanahan, D. (2022). Hallmarks of Cancer: New Dimensions. Cancer Discovery, 12(1), 31–46. https://doi.org/10.1158/2159-8290.CD-21-1059
Husmann, D., & Gozani, O. (2019). Histone lysine methyltransferases in biology and disease. Nature Structural & Molecular Biology, 26(10), 880–889. https://doi.org/10.1038/s41594-019-0298-7
Jarrold, J., & Davies, C. C. (2019). PRMTs and Arginine Methylation: Cancer’s Best-Kept Secret? Trends in Molecular Medicine, 25(11), 993–1009. https://doi.org/10.1016/j.molmed.2019.05.007
Lee, D. D., Komosa, M., Nunes, N. M., & Tabori, U. (2020). DNA methylation of the TERT promoter and its impact on human cancer. Current Opinion in Genetics & Development, 60, 17–24. https://doi.org/10.1016/j.gde.2020.02.003
Lowe, B. R., Maxham, L. A., Hamey, J. J., Wilkins, M. R., & Partridge, J. F. (2019). Histone H3 Mutations: An Updated View of Their Role in Chromatin Deregulation and Cancer. Cancers, 11(5), 660. https://doi.org/10.3390/cancers11050660
Parreno, V., Martinez, A.-M., & Cavalli, G. (2022). Mechanisms of Polycomb group protein function in cancer. Cell Research, 32(3), 231–253. https://doi.org/10.1038/s41422-021-00606-6
Piunti, A., & Shilatifard, A. (2021). The roles of Polycomb repressive complexes in mammalian development and cancer. Nature Reviews. Molecular Cell Biology, 22(5), 326–345. https://doi.org/10.1038/s41580-021-00341-1
Primac, I., Penning, A., & Fuks, F. (2022). Cancer epitranscriptomics in a nutshell. Current Opinion in Genetics & Development, 75, 101924. https://doi.org/10.1016/j.gde.2022.101924
Sendinc, E., & Shi, Y. (2023). RNA m6A methylation across the transcriptome. Molecular Cell, 83(3), 428–441. https://doi.org/10.1016/j.molcel.2023.01.006
Ushijima, T., Clark, S. J., & Tan, P. (2021). Mapping genomic and epigenomic evolution in cancer ecosystems. Science (New York, N.Y.), 373(6562), 1474–1479. https://doi.org/10.1126/science.abh1645
Zhao, S., Allis, C. D., & Wang, G. G. (2021). The language of chromatin modification in human cancers. Nature Reviews. Cancer, 21(7), 413–430. https://doi.org/10.1038/s41568-021-00357-x
13.5 Post-transcriptional process and cancer
Bradley, R. K., & Anczuków, O. (2023). RNA splicing dysregulation and the hallmarks of cancer. Nature Reviews. Cancer, 23(3), 135–155. https://doi.org/10.1038/s41568-022-00541-7
Destefanis, F., Manara, V., & Bellosta, P. (2020). Myc as a Regulator of Ribosome Biogenesis and Cell Competition: A Link to Cancer. International Journal of Molecular Sciences, 21(11), 4037. https://doi.org/10.3390/ijms21114037
Frezza, V., Chellini, L., Del Verme, A., & Paronetto, M. P. (2023). RNA Editing in Cancer Progression. Cancers, 15(21), 5277. https://doi.org/10.3390/cancers15215277
Masui, K., Harachi, M., Cavenee, W. K., Mischel, P. S., & Shibata, N. (2020). mTOR complex 2 is an integrator of cancer metabolism and epigenetics. Cancer Letters, 478, 1–7. https://doi.org/10.1016/j.canlet.2020.03.001
Ngeow, J., & Eng, C. (2020). PTEN in Hereditary and Sporadic Cancer. Cold Spring Harbor Perspectives in Medicine, 10(4), a036087. https://doi.org/10.1101/cshperspect.a036087
Robichaud, N., Sonenberg, N., Ruggero, D., & Schneider, R. J. (2019). Translational Control in Cancer. Cold Spring Harbor Perspectives in Biology, 11(7), a032896. https://doi.org/10.1101/cshperspect.a032896
Rubio, A., Garland, G. D., Sfakianos, A., Harvey, R. F., & Willis, A. E. (2022). Aberrant protein synthesis and cancer development: The role of canonical eukaryotic initiation, elongation and termination factors in tumorigenesis. Seminars in Cancer Biology, 86(Pt 3), 151–165. https://doi.org/10.1016/j.semcancer.2022.04.006
Vervoort, S. J., Devlin, J. R., Kwiatkowski, N., Teng, M., Gray, N. S., & Johnstone, R. W. (2022). Targeting transcription cycles in cancer. Nature Reviews Cancer, 22(1), 5–24. https://doi.org/10.1038/s41568-021-00411-8
13.6 Regulatory RNAs and cancer
Agostini, M., Ganini, C., Candi, E., & Melino, G. (2020). The role of noncoding RNAs in epithelial cancer. Cell Death Discovery, 6, 13. https://doi.org/10.1038/s41420-020-0247-6
Elliott, K., & Larsson, E. (2021). Non-coding driver mutations in human cancer. Nature Reviews. Cancer, 21(8), 500–509. https://doi.org/10.1038/s41568-021-00371-z
Kristensen, L. S., Jakobsen, T., Hager, H., & Kjems, J. (2022). The emerging roles of circRNAs in cancer and oncology. Nature Reviews. Clinical Oncology, 19(3), 188–206. https://doi.org/10.1038/s41571-021-00585-y
Nemeth, K., Bayraktar, R., Ferracin, M., & Calin, G. A. (2024). Non-coding RNAs in disease: From mechanisms to therapeutics. Nature Reviews. Genetics, 25(3), 211–232. https://doi.org/10.1038/s41576-023-00662-1
O’Brien, S. J., Bishop, C., Hallion, J., Fiechter, C., Scheurlen, K., Paas, M., Burton, J., & Galandiuk, S. (2020). Long non-coding RNA (lncRNA) and epithelial-mesenchymal transition (EMT) in colorectal cancer: A systematic review. Cancer Biology & Therapy, 21(9), 769–781. https://doi.org/10.1080/15384047.2020.1794239
Otmani, K., & Lewalle, P. (2021). Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications. Frontiers in Oncology, 11, 708765. https://doi.org/10.3389/fonc.2021.708765
Otmani, K., Rouas, R., Berehab, M., & Lewalle, P. (2024). The regulatory mechanisms of oncomiRs in cancer. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 171, 116165. https://doi.org/10.1016/j.biopha.2024.116165
Shi, X., Wang, B., Feng, X., Xu, Y., Lu, K., & Sun, M. (2020). circRNAs and Exosomes: A Mysterious Frontier for Human Cancer. Molecular Therapy. Nucleic Acids, 19, 384–392. https://doi.org/10.1016/j.omtn.2019.11.023